Hepatitis C Virus Inhibitors

ABSTRACT

The present disclosure relates to compounds, compositions and methods for the treatment of hepatitis C virus (HCV) infection. Also disclosed are pharmaceutical compositions containing such compounds and methods for using these compounds in the treatment of HCV infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Continuation application claims the benefit of U.S. Non-Provisionalapplication, U.S. Ser. No. 12/701,919 filed Feb. 8, 2010, now allowed,which claims the benefit of U.S. Provisional Application, U.S. Ser. No.61/153,186 filed Feb. 17, 2009, now expired, hereby incorporated byreference in their entireties.

The present disclosure is generally directed to antiviral compounds, andmore specifically directed to compounds which can inhibit the functionof the NS5A protein encoded by Hepatitis C virus (HCV), compositionscomprising such compounds, and methods for inhibiting the function ofthe NS5A protein.

HCV is a major human pathogen, infecting an estimated 170 millionpersons worldwide—roughly five times the number infected by humanimmunodeficiency virus type 1. A substantial fraction of these HCVinfected individuals develop serious progressive liver disease,including cirrhosis and hepatocellular carcinoma.

The current standard of care for HCV, which employs a combination ofpegylated-interferon and ribavirin, has a non-optimal success rate inachieving sustained viral response and causes numerous side effects.Thus, there is a clear and long-felt need to develop effective therapiesto address this undermet medical need.

HCV is a positive-stranded RNA virus. Based on a comparison of thededuced amino acid sequence and the extensive similarity in the 5′untranslated region, HCV has been classified as a separate genus in theFlaviviridae family. All members of the Flaviviridae family haveenveloped virions that contain a positive stranded RNA genome encodingall known virus-specific proteins via translation of a single,uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encodedamino acid sequence throughout the HCV genome due to the high error rateof the encoded RNA dependent RNA polymerase which lacks a proof-readingcapability. At least six major genotypes have been characterized, andmore than 50 subtypes have been described with distribution worldwide.The clinical significance of the genetic heterogeneity of HCV hasdemonstrated a propensity for mutations to arise during monotherapytreatment, thus additional treatment options for use are desired. Thepossible modulator effect of genotypes on pathogenesis and therapyremains elusive.

The single strand HCV RNA genome is approximately 9500 nucleotides inlength and has a single open reading frame (ORF) encoding a single largepolyprotein of about 3000 amino acids. In infected cells, thispolyprotein is cleaved at multiple sites by cellular and viral proteasesto produce the structural and non-structural (NS) proteins. In the caseof HCV, the generation of mature non-structural proteins (NS2, NS3,NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. Thefirst one is believed to be a metalloprotease and cleaves at the NS2-NS3junction; the second one is a serine protease contained within theN-terminal region of NS3 (also referred to herein as NS3 protease) andmediates all the subsequent cleavages downstream of NS3, both in cis, atthe NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B,NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiplefunctions by both acting as a cofactor for the NS3 protease andassisting in the membrane localization of NS3 and other viral replicasecomponents. The formation of a NS3-NS4A complex is necessary for properprotease activity resulting in increased proteolytic efficiency of thecleavage events. The NS3 protein also exhibits nucleoside triphosphataseand RNA helicase activities. NS5B (also referred to herein as HCVpolymerase) is a RNA-dependent RNA polymerase that is involved in thereplication of HCV with other HCV proteins, including NS5A, in areplicase complex.

Compounds useful for treating HCV-infected patients are desired whichselectively inhibit HCV viral replication. In particular, compoundswhich are effective to inhibit the function of the NS5A protein aredesired. The HCV NS5A protein is described, for example, in thefollowing references: S. L. Tan, et al., Virology, 284:1-12 (2001);K.-J. Park, et al., J. Biol. Chem., 30711-30718 (2003); T. L.Tellinghuisen, et al., Nature, 435, 374 (2005); R. A. Love, et al., J.Virol, 83, 4395 (2009); N. Appel, et al., J. Biol. Chem., 281, 9833(2006); L. Huang, J. Biol. Chem., 280, 36417 (2005); C. Rice, et al.,WO2006093867.

In a first aspect the present disclosure provides a compound of Formula(I)

or a pharmaceutically acceptable salt thereof, wherein

each m is independently 0 or 1;

each n is independently 0 or 1;

L is a bond or is selected from

wherein each group is drawn with its left end attached to thebenzimidazole and its right end attached to R¹;

R¹ is selected from

each R² is independently selected from alkyl and halo;

each R³ is independently selected from hydrogen and —C(O)R⁷;

R⁴ is alkyl;

R⁵ and R⁶ are independently selected from hydrogen, alkyl, cyanoalkyl,and halo, or

R⁵ and R⁶, together with the carbon atoms to which they are attached,form a six- or seven-membered ring optionally containing one heteroatomselected from nitrogen and oxygen and optionally containing anadditional double bond; and

each R⁷ is independently selected from alkoxy, alkyl, arylalkoxy,arylalkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl,heterocyclylalkyl, (NR^(c)R^(d))alkenyl, and (NR^(c)R^(d))alkyl.

In a first embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein L is a bond.

In a second embodiment of the first aspect R¹ is

In a third embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein L is

In a fourth embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein L is

In a fifth embodiment R¹ is selected from

In a sixth embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein L is

In a seventh embodiment L is selected from

In an eighth embodiment R¹ is

In a ninth embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein L is

In a tenth embodiment R¹ is

In an eleventh embodiment of the first aspect the present disclosureprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, wherein L is

wherein L is selected from wherein each group is drawn with its left endattached to the benzimidazole and its right end attached to R¹.

In a twelfth embodiment R¹ is

In a second aspect the present disclosure provides a compound of Formula(II)

or a pharmaceutically acceptable salt thereof, wherein

each m is independently 0 or 1;

each n is independently 0 or 1;

L is a bond or is selected from

R¹ is selected from

each R² is independently selected from alkyl and halo;

each R³ is independently selected from hydrogen and —C(O)R⁷;

R⁴ is alkyl;

R⁵ and R⁶ are independently hydrogen or halo, or

R⁵ and R⁶, together with the carbon atoms to which they are attached,form a six- or seven-membered ring optionally containing one heteroatomselected from nitrogen and oxygen and optionally containing anadditional double bond; and

each R⁷ is independently selected from alkoxy, alkyl, arylalkyl,cycloalkyl, heterocyclyl, heterocyclylalkyl, (NR^(c)R^(d))alkenyl, and(NR^(c)R^(d))alkyl.

In a third aspect the present disclosure provides a compositioncomprising a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier. In a firstembodiment of the third aspect the composition further comprises one ortwo additional compounds having anti-HCV activity. In a secondembodiment of the third aspect at least one of the additional compoundsis an interferon or a ribavirin. In a third embodiment the interferon isselected from interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastiod interferon tau.

In a fourth embodiment of the third aspect the present disclosureprovides a composition comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, a pharmaceutically acceptablecarrier, and one or two additional compounds having anti-HCV activity,wherein at least one of the additional compounds is selected frominterleukin 2, interleukin 6, interleukin 12, a compound that enhancesthe development of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.

In a fifth embodiment of the third aspect the present disclosureprovides a composition comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, a pharmaceutically acceptablecarrier, and one or two additional compounds having anti-HCV activity,wherein at least one of the additional compounds is effective to inhibitthe function of a target selected from HCV metalloprotease, HCV serineprotease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCVassembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment ofan HCV infection.

In a fourth aspect the present disclosure provides a method of treatingan HCV infection in a patient, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof. In a first embodiment of thefourth aspect the method further comprises administering one or twoadditional compounds having anti-HCV activity prior to, after orsimultaneously with the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof. In a second embodiment of the fourth aspect atleast one of the additional compounds is an interferon or a ribavirin.In a third embodiment of the fourth aspect the interferon is selectedfrom interferon alpha 2B, pegylated interferon alpha, consensusinterferon, interferon alpha 2A, and lymphoblastiod interferon tau.

In a fourth embodiment of the fourth aspect the present disclosureprovides a method of treating an HCV infection in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and one or two additional compounds having anti-HCV activity prior to,after or simultaneously with the compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein at least one of theadditional compounds is selected from interleukin 2, interleukin 6,interleukin 12, a compound that enhances the development of a type 1helper T cell response, interfering RNA, anti-sense RNA, Imiqimod,ribavirin, an inosine 5′-monophospate dehydrogenase inhibitor,amantadine, and rimantadine.

In a fifth embodiment of the fourth aspect the present disclosureprovides a method of treating an HCV infection in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and one or two additional compounds having anti-HCV activity prior to,after or simultaneously with the compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein at least one of theadditional compounds is effective to inhibit the function of a targetselected from HCV metalloprotease, HCV serine protease, HCV polymerase,HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCVNS5A protein, and IMPDH for the treatment of an HCV infection.

Other embodiments of the present disclosure may comprise suitablecombinations of two or more of embodiments and/or aspects disclosedherein.

Yet other embodiments and aspects of the disclosure will be apparentaccording to the description provided below.

The compounds of the present disclosure also exist as tautomers;therefore the present disclosure also encompasses all tautomeric forms.

The description of the present disclosure herein should be construed incongruity with the laws and principals of chemical bonding.

It should be understood that the compounds encompassed by the presentdisclosure are those that are suitably stable for use as pharmaceuticalagent.

It is intended that the definition of any substituent or variable (e.g.,R² and R⁴) at a particular location in a molecule be independent of itsdefinitions elsewhere in that molecule. For example, when n is 2, eachof the two R² groups may be the same or different.

All patents, patent applications, and literature references cited in thespecification are herein incorporated by reference in their entirety. Inthe case of inconsistencies, the present disclosure, includingdefinitions, will prevail.

As used in the present specification, the following terms have themeanings indicated:

As used herein, the singular forms “a”, “an”, and “the” include pluralreference unless the context clearly dictates otherwise.

Unless stated otherwise, all aryl, cycloalkyl, and heterocyclyl groupsof the present disclosure may be substituted as described in each oftheir respective definitions. For example, the aryl part of an arylalkylgroup may be substituted as described in the definition of the term‘aryl’.

The term “alkoxy,” as used herein, refers to an alkyl group attached tothe parent molecular moiety through an oxygen atom.

The term “alkoxycarbonyl,” as used herein, refers to an alkoxy groupattached to the parent molecular moiety through a carbonyl group.

The term “alkyl,” as used herein, refers to a group derived from astraight or branched chain saturated hydrocarbon containing from one tosix carbon atoms. In the compounds of the present disclosure, when m is1 and R⁴ is alkyl, the alkyl can optionally form a fused three- orfour-membered ring with an adjacent carbon atom to provide one of thestructures shown below:

where z is 1 or 2, w is 0, 1, or 2, and R⁵⁰ is alkyl. When w is 2, thetwo R⁵⁰ alkyl groups may be the same or different.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclicfused ring system wherein one or both of the rings is a phenyl group.Bicyclic fused ring systems consist of a phenyl group fused to a four-to six-membered aromatic or non-aromatic carbocyclic ring. The arylgroups of the present disclosure can be attached to the parent molecularmoiety through any substitutable carbon atom in the group.Representative examples of aryl groups include, but are not limited to,indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The arylgroups of the present disclosure are optionally substituted with one,two, three, four, or five substituents independently selected fromalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second arylgroup, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy,haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,hydroxy, hydroxyalkyl, nitro, —NR^(x)R^(y), (NR^(x)R^(y))alkyl, oxo, and—P(O)OR₂, wherein each R is independently selected from hydrogen andalkyl; and wherein the alkyl part of the arylalkyl and theheterocyclylalkyl are unsubstituted and wherein the second aryl group,the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, theheterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and theheterocyclylcarbonyl are further optionally substituted with one, two,or three substituents independently selected from alkoxy, alkyl, cyano,halo, haloalkoxy, haloalkyl, and nitro.

The term “arylalkoxy,” as used herein, refers to an arylalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “arylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three aryl groups. The alkyl part of thearylalkyl is further optionally substituted with one or two additionalgroups independently selected from alkoxy, alkylcarbonyloxy, halo,haloalkoxy, haloalkyl, heterocyclyl, hydroxy, and —NR^(c)R^(d), whereinthe heterocyclyl is further optionally substituted with one or twosubstituents independently selected from alkoxy, alkyl, unsubstitutedaryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo,haloalkoxy, haloalkyl, hydroxy, —NR^(x)R^(Y), and oxo.

The term “carbonyl,” as used herein, refers to —C(O)—.

The term “cyanoalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three cyano groups.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic,hydrocarbon ring system having three to seven carbon atoms and zeroheteroatoms. Representative examples of cycloalkyl groups include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl. The cycloalkyl groups of the present disclosure areoptionally substituted with one, two, three, four, or five substituentsindependently selected from alkoxy, alkyl, aryl, cyano, halo,haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, nitro, and—NR^(x)R^(y), wherein the aryl and the heterocyclyl are furtheroptionally substituted with one, two, or three substituentsindependently selected from alkoxy, alkyl, cyano, halo, haloalkoxy,haloalkyl, hydroxy, and nitro.

The term “(cycloalkyl)alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three cycloalkyl groups.

The term “cycloalkyloxy,” as used herein, refers to a cycloalkyl groupattached to the parent molecular moiety through an oxygen atom.

The term “cycloalkyloxycarbonyl,” as used herein, refers to acycloalkyloxy group attached to the parent molecular moiety through acarbonyl group.

The terms “halo” and “halogen,” as used herein, refer to F, Br, Cl, orI.

The term “heterocyclyl,” as used herein, refers to a four-, five-, six-,or seven-membered ring containing one, two, three, or four heteroatomsindependently selected from nitrogen, oxygen, and sulfur. Thefour-membered ring has zero double bonds, the five-membered ring haszero to two double bonds, and the six- and seven-membered rings havezero to three double bonds. The term “heterocyclyl” also includesbicyclic groups in which the heterocyclyl ring is fused to anothermonocyclic heterocyclyl group, or a four- to six-membered aromatic ornon-aromatic carbocyclic ring; as well as bridged bicyclic groups suchas 7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oct-2-yl, and2-azabicyclo[2.2.2]oct-3-yl. The heterocyclyl groups of the presentdisclosure can be attached to the parent molecular moiety through anycarbon atom or nitrogen atom in the group. Examples of heterocyclylgroups include, but are not limited to, benzothienyl, furyl, imidazolyl,indolinyl, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl,morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl,pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, quinolinyl, thiazolyl,thienyl, and thiomorpholinyl. The heterocyclyl groups of the presentdisclosure are optionally substituted with one, two, three, four, orfive substituents independently selected from alkoxy, alkoxyalkyl,alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl,cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group,heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro,—NR^(x)R^(y), (NR^(x)R^(y))alkyl, and oxo, wherein the alkyl part of thearylalkyl and the heterocyclylalkyl are unsubstituted and wherein thearyl, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl,the second heterocyclyl group, and the heterocyclyl part of theheterocyclylalkyl and the heterocyclylcarbonyl are further optionallysubstituted with one, two, or three substituents independently selectedfrom alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “heterocyclylalkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three heterocyclyl groups. The alkyl partof the heterocyclylalkyl is further optionally substituted with one ortwo additional groups independently selected from alkoxy,alkylcarbonyloxy, aryl, halo, haloalkoxy, haloalkyl, hydroxy, and—NR^(c)R^(d), wherein the aryl is further optionally substituted withone or two substituents independently selected from alkoxy, alkyl,unsubstituted aryl, unsubstituted arylalkoxy, unsubstitutedarylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and—NR^(x)R^(y).

The term “—NR^(c)R^(d),” as used herein, refers to two groups, R^(c) andR^(d), which are attached to the parent molecular moiety through anitrogen atom. R^(c) and R^(d) are independently selected from hydrogen,alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl,alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl,arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,cycloalkyl, cycloalkyloxycarbonyl, cycloalkylsulfonyl, formyl,haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl,heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl,heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^(e)R^(f))alkyl,(NR^(e)R^(f))alkylcarbonyl, (NR^(e)R^(f))carbonyl,(NR^(e)R^(f))sulfonyl, —C(NCN)OR′, and —C(NCN)NR^(x)R^(y), wherein R′ isselected from alkyl and unsubstituted phenyl, and wherein the alkyl partof the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and theheterocyclylalkylcarbonyl are further optionally substituted with one—NR^(e)R^(f) group; and wherein the aryl, the aryl part of thearylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, thearylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, theheterocyclyl, and the heterocyclyl part of theheterocyclylalkoxycarbonyl, the heterocyclylalkyl, theheterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and theheterocyclyloxycarbonyl are further optionally substituted with one,two, or three substituents independently selected from alkoxy, alkyl,cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “(NR^(c)R^(d))alkenyl,” as used herein, refers to

wherein R^(c) and R^(d) are as defined herein and each R^(q) isindependently hydrogen or C₁₋₃ alkyl.

The term “(NR^(c)R^(d))alkyl,” as used herein, refers to an alkyl groupsubstituted with one, two, or three —NR^(c)R^(d) groups. The alkyl partof the (NR^(c)R^(d))alkyl is further optionally substituted with one ortwo additional groups selected from alkoxy, alkoxyalkylcarbonyl,alkoxycarbonyl, alkylsulfanyl, arylalkoxycarbonyl, carboxy, cycloalkyl,heterocyclyl, heterocyclylcarbonyl, hydroxy, and (NR^(e)R^(f))carbonyl;wherein the heterocyclyl is further optionally substituted with one,two, three, four, or five substituents independently selected fromalkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “—NR^(e)R^(f),” as used herein, refers to two groups, R^(e) andR^(f), which are attached to the parent molecular moiety through anitrogen atom. R^(e) and R^(f) are independently selected from hydrogen,alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstitutedcycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstitutedheterocyclyl, unsubstituted heterocyclylalkyl, (NR^(x)R^(y))alkyl, and(NR^(x)R^(y))carbonyl.

The term “—NR^(x)R^(y),” as used herein, refers to two groups, R^(x) andR^(y), which are attached to the parent molecular moiety through anitrogen atom. R^(x) and R^(y) are independently selected from hydrogen,alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstitutedarylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl,unsubstituted heterocyclyl, and (NR^(x′)R^(y′))carbonyl, wherein R^(x′)and R^(y′) are independently selected from hydrogen and alkyl.

Asymmetric centers exist in the compounds of the present disclosure.These centers are designated by the symbols “R” or “S”, depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the disclosure encompasses all stereochemicalisomeric forms, or mixtures thereof, which possess the ability toinhibit NS5A. Individual stereoisomers of compounds can be preparedsynthetically from commercially available starting materials whichcontain chiral centers or by preparation of mixtures of enantiomericproducts followed by separation such as conversion to a mixture ofdiastereomers followed by separation or recrystallization,chromatographic techniques, or direct separation of enantiomers onchiral chromatographic columns. Starting compounds of particularstereochemistry are either commercially available or can be made andresolved by techniques known in the art.

Certain compounds of the present disclosure may also exist in differentstable conformational forms which may be separable. Torsional asymmetrydue to restricted rotation about an asymmetric single bond, for examplebecause of steric hindrance or ring strain, may permit separation ofdifferent conformers. The present disclosure includes eachconformational isomer of these compounds and mixtures thereof.

The term “compounds of the present disclosure”, and equivalentexpressions, are meant to embrace compounds of Formula (I), andpharmaceutically acceptable enantiomers, diastereomers, and saltsthereof. Similarly, references to intermediates are meant to embracetheir salts where the context so permits.

The present disclosure is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds may have a variety of potential uses,for example as standards and reagents in determining biologicalactivity. In the case of stable isotopes, such compounds may have thepotential to favorably modify biological, pharmacological, orpharmacokinetic properties.

The compounds of the present disclosure can exist as pharmaceuticallyacceptable salts. The term “pharmaceutically acceptable salt,” as usedherein, represents salts or zwitterionic forms of the compounds of thepresent disclosure which are water or oil-soluble or dispersible, whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of patients without excessive toxicity,irritation, allergic response, or other problem or complicationcommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use. The salts can be prepared during the final isolationand purification of the compounds or separately by reacting a suitablenitrogen atom with a suitable acid. Representative acid addition saltsinclude acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate;digluconate, dihydrobromide, dihydrochloride, dihydroiodide,glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,lactate, maleate, mesitylenesulfonate, methanesulfonate,naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate,palmoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,phosphate, glutamate, bicarbonate, para-toluenesulfonate, andundecanoate. Examples of acids which can be employed to formpharmaceutically acceptable addition salts include inorganic acids suchas hydrochloric, hydrobromic, sulfuric, and phosphoric, and organicacids such as oxalic, maleic, succinic, and citric.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reacting a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of pharmaceutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,and N,N′-dibenzylethylenediamine. Other representative organic aminesuseful for the formation of base addition salts include ethylenediamine,ethanolamine, diethanolamine, piperidine, and piperazine.

When it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as pharmaceuticallyacceptable salts thereof, may be administered as the raw chemical, it ispossible to present the active ingredient as a pharmaceuticalcomposition. Accordingly, the disclosure further provides pharmaceuticalcompositions, which include therapeutically effective amounts ofcompounds of formula (I) or pharmaceutically acceptable salts thereof,and one or more pharmaceutically acceptable carriers, diluents, orexcipients. The term “therapeutically effective amount,” as used herein,refers to the total amount of each active component that is sufficientto show a meaningful patient benefit, e.g., a reduction in viral load.When applied to an individual active ingredient, administered alone, theterm refers to that ingredient alone. When applied to a combination, theterm refers to combined amounts of the active ingredients that result inthe therapeutic effect, whether administered in combination, serially,or simultaneously. The compounds of formula (I) and pharmaceuticallyacceptable salts thereof, are as described above. The carrier(s),diluent(s), or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the present disclosure there is also provided a process for thepreparation of a pharmaceutical formulation including admixing acompound of formula (I), or a pharmaceutically acceptable salt thereof,with one or more pharmaceutically acceptable carriers, diluents, orexcipients. The term “pharmaceutically acceptable,” as used herein,refers to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of patients without excessive toxicity,irritation, allergic response, or other problem or complicationcommensurate with a reasonable benefit/risk ratio, and are effective fortheir intended use.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Dosage levels of between about 0.01 and about 250 milligram per kilogram(“mg/kg”) body weight per day, preferably between about 0.05 and about100 mg/kg body weight per day of the compounds of the present disclosureare typical in a monotherapy for the prevention and treatment of HCVmediated disease. Typically, the pharmaceutical compositions of thisdisclosure will be administered from about 1 to about 5 times per day oralternatively, as a continuous infusion. Such administration can be usedas a chronic or acute therapy. The amount of active ingredient that maybe combined with the carrier materials to produce a single dosage formwill vary depending on the condition being treated, the severity of thecondition, the time of administration, the route of administration, therate of excretion of the compound employed, the duration of treatment,and the age, gender, weight, and condition of the patient. Preferredunit dosage formulations are those containing a daily dose or sub-dose,as herein above recited, or an appropriate fraction thereof, of anactive ingredient. Treatment may be initiated with small dosagessubstantially less than the optimum dose of the compound. Thereafter,the dosage is increased by small increments until the optimum effectunder the circumstances is reached. In general, the compound is mostdesirably administered at a concentration level that will generallyafford antivirally effective results without causing any harmful ordeleterious side effects.

When the compositions of this disclosure comprise a combination of acompound of the present disclosure and one or more additionaltherapeutic or prophylactic agent, both the compound and the additionalagent are usually present at dosage levels of between about 10 to 150%,and more preferably between about 10 and 80% of the dosage normallyadministered in a monotherapy regimen.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual, ortransdermal), vaginal, or parenteral (including subcutaneous,intracutaneous, intramuscular, intra-articular, intrasynovial,intrasternal, intrathecal, intralesional, intravenous, or intradermalinjections or infusions) route. Such formulations may be prepared by anymethod known in the art of pharmacy, for example by bringing intoassociation the active ingredient with the carrier(s) or excipient(s).Oral administration or administration by injection are preferred.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilemulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing, and coloringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate, or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate, or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents, and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, and the like. Lubricantsused in these dosage forms include sodium oleate, sodium chloride, andthe like. Disintegrators include, without limitation, starch, methylcellulose, agar, betonite, xanthan gum, and the like. Tablets areformulated, for example, by preparing a powder mixture, granulating orslugging, adding a lubricant and disintegrant, and pressing intotablets. A powder mixture is prepared by mixing the compound, suitablecomminuted, with a diluent or base as described above, and optionally,with a binder such as carboxymethylcellulose, an aliginate, gelating, orpolyvinyl pyrrolidone, a solution retardant such as paraffin, aresorption accelerator such as a quaternary salt and/or and absorptionagent such as betonite, kaolin, or dicalcium phosphate. The powdermixture can be granulated by wetting with a binder such as syrup, starchpaste, acadia mucilage, or solutions of cellulosic or polymericmaterials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc, ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present disclosure can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material, and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic vehicle. Solubilizers andemulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylenesorbitol ethers, preservatives, flavor additive such as peppermint oilor natural sweeteners, or saccharin or other artificial sweeteners, andthe like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax, or the like.

The compounds of formula (I), and pharmaceutically acceptable saltsthereof, can also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesicles,and multilamellar vesicles. Liposomes can be formed from a variety ofphopholipids, such as cholesterol, stearylamine, or phophatidylcholines.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be delivered by the use of monoclonal antibodies asindividual carriers to which the compound molecules are coupled. Thecompounds may also be coupled with soluble polymers as targetable drugcarriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxypropylmethacrylamidephenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research 1986,3(6), 318.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a course powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or nasal drops, include aqueous or oilsolutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and soutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavoringagents.

The term “patient” includes both human and other mammals.

The term “treating” refers to: (i) preventing a disease, disorder orcondition from occurring in a patient that may be predisposed to thedisease, disorder, and/or condition but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, disorder, or condition, i.e.,arresting its development; and (iii) relieving the disease, disorder, orcondition, i.e., causing regression of the disease, disorder, and/orcondition.

The compounds of the present disclosure can also be administered with acyclosporin, for example, cyclosporin A. Cyclosporin A has been shown tobe active against HCV in clinical trials (Hepatology 2003, 38, 1282;Biochem. Biophys. Res. Commun. 2004, 313, 42; J. Gastroenterol. 2003,38, 567).

Table 1 below lists some illustrative examples of compounds that can beadministered with the compounds of this disclosure. The compounds of thedisclosure can be administered with other anti-HCV activity compounds incombination therapy, either jointly or separately, or by combining thecompounds into a composition.

TABLE 1 Type of Inhibitor or Brand Name Physiological Class TargetSource Company NIM811 Cyclophilin inhibitors Novartis DebiopharmDebio-025 Zadaxin Immunomodulator SciClone Suvus Methylene blueBioenvision Actilon (CPG10101) TLR9 agonist Coley Batabulin (T67)Anticancer β-Tubulin inhibitor Tularik Inc., South San Francisco, CAISIS 14803 Antiviral Antisense ISIS Pharmaceuticals Inc, Carlsbad, CA/Elan Pharmaceuticals Inc., New York, NY Summetrel Antiviral AntiviralEndo Pharmaceuticals Holdings Inc., Chadds Ford, PA GS-9132 (ACH-806)Antiviral HCV inhibitor Achillion/Gilead Pyrazolopyrimidine AntiviralHCV inhibitors Arrow Therapeutics compounds and salts Ltd. From WO2005/047288 May 26, 2005 Levovirin Antiviral IMPDH inhibitor RibapharmInc., Costa Mesa, CA Merimepodib Antiviral IMPDH inhibitor Vertex(VX-497) Pharmaceuticals Inc., Cambridge, MA XTL-6865 AntiviralMonoclonal antibody XTL (XTL-002) Biopharmaceuticals Ltd., Rehovot,Israel Telaprevir Antiviral NS3 serine protease Vertex (VX-950,inhibitor Pharmaceuticals Inc., LY-570310) Cambridge, MA/Eli Lilly andCo., Inc., Indianapolis, IN HCV-796 Antiviral NS5B replicaseWyeth/Viropharma inhibitor NM-283 Antiviral NS5B replicaseIdenix/Novartis inhibitor GL-59728 Antiviral NS5B replicase GeneLabs/Novartis inhibitor GL-60667 Antiviral NS5B replicase GeneLabs/Novartis inhibitor 2′C MeA Antiviral NS5B replicase Gileadinhibitor PSI 6130 Antiviral NS5B replicase Roche inhibitor R1626Antiviral NS5B replicase Roche inhibitor 2′C Methyl Antiviral NS5Breplicase Merck adenosine inhibitor JTK-003 Antiviral RdRp inhibitorJapan Tobacco Inc., Tokyo, Japan Levovirin Antiviral Ribavirin ICNPharmaceuticals, Costa Mesa, CA Ribavirin Antiviral RibavirinSchering-Plough Corporation, Kenilworth, NJ Viramidine AntiviralRibavirin prodrug Ribapharm Inc., Costa Mesa, CA Heptazyme AntiviralRibozyme Ribozyme Pharmaceuticals Inc., Boulder, CO BILN-2061 AntiviralSerine protease Boehringer Ingelheim inhibitor Pharma KG, Ingelheim,Germany SCH 503034 Antiviral Serine protease Schering-Plough inhibitorZadazim Immune modulator Immune modulator SciClone Pharmaceuticals Inc.,San Mateo, CA Ceplene Immunomodulator Immune modulator MaximPharmaceuticals Inc., San Diego, CA CELLCEPT ® Immunosuppressant HCV IgGF. Hoffmann-La immunosuppressant Roche LTD, Basel, Switzerland CivacirImmunosuppressant HCV IgG Nabi immunosuppressant BiopharmaceuticalsInc., Boca Raton, FL Albuferon-α Interferon Albumin IFN-α2b Human GenomeSciences Inc., Rockville, MD Infergen A Interferon IFN alfacon-1InterMune Pharmaceuticals Inc., Brisbane, CA Omega IFN Interferon IFN-ωIntarcia Therapeutics IFN-β and EMZ701 Interferon IFN-β and EMZ701Transition Therapeutics Inc., Ontario, Canada REBIF ® Interferon IFN-β1aSerono, Geneva, Switzerland Roferon A Interferon IFN-α2a F. Hoffmann-LaRoche LTD, Basel, Switzerland Intron A Interferon IFN-α2bSchering-Plough Corporation, Kenilworth, NJ Intron A and ZadaxinInterferon IFN-α2b/α1-thymosin RegeneRx Biopharma. Inc., Bethesda, MD/SciClone Pharmaceuticals Inc, San Mateo, CA Rebetron InterferonIFN-α2b/ribavirin Schering-Plough Corporation, Kenilworth, NJ ActimmuneInterferon INF-γ InterMune Inc., Brisbane, CA Interferon-β InterferonInterferon-β-1a Serono Multiferon Interferon Long lasting IFNViragen/Valentis Wellferon Interferon Lymphoblastoid IFN-GlaxoSmithKline plc, αn1 Uxbridge, UK Omniferon Interferon natural IFN-αViragen Inc., Plantation, FL Pegasys Interferon PEGylated IFN-α2a F.Hoffmann-La Roche LTD, Basel, Switzerland Pegasys and Ceplene InterferonPEGylated IFN- Maxim α2a/immune Pharmaceuticals Inc., modulator SanDiego, CA Pegasys and Interferon PEGylated IFN- F. Hoffmann-La Ribavirinα2a/ribavirin Roche LTD, Basel, Switzerland PEG-Intron InterferonPEGylated IFN-α2b Schering-Plough Corporation, Kenilworth, NJPEG-Intron/ Interferon PEGylated IFN- Schering-Plough Ribavirinα2b/ribavirin Corporation, Kenilworth, NJ IP-501 Liver protectionAntifibrotic Indevus Pharmaceuticals Inc., Lexington, MA IDN-6556 Liverprotection Caspase inhibitor Idun Pharmaceuticals Inc., San Diego, CAITMN-191 Antiviral Serine protease InterMune (R-7227) inhibitorPharmaceuticals Inc., Brisbane, CA GL-59728 Antiviral NS5B replicaseGenelabs inhibitor ANA-971 Antiviral TLR-7 agonist Anadys BoceprevirAntiviral Serine protease Schering-Plough inhibitor TMS-435 AntiviralSerine protease Tibotec BVBA, inhibitor Mechelen, Belgium BI-201335Antiviral Serine protease Boehringer Ingelheim inhibitor Pharma KG,Ingelheim, Germany MK-7009 Antiviral Serine protease Merck inhibitorPF-00868554 Antiviral Replicase inhibitor Pfizer ANA598 AntiviralNon-Nucleoside Anadys NS5B polymerase Pharmaceuticals, Inc., inhibitorSan Diego, CA, USA IDX375 Antiviral Non-Nucleoside Idenix replicaseinhibitor Pharmaceuticals, Cambridge, MA, USA BILB 1941 Antiviral NS5Bpolymerase Boehringer Ingelheim inhibitor Canada Ltd R&D, Laval, QC,Canada PSI-7851 Antiviral Nucleoside Pharmasset, polymerase inhibitorPrinceton, NJ, USA VCH-759 Antiviral NS5B polymerase ViroChem Pharmainhibitor VCH-916 Antiviral NS5B polymerase ViroChem Pharma inhibitorGS-9190 Antiviral NS5B polymerase Gilead inhibitor Peg-interferon lamdaAntiviral Interferon ZymoGenetics/ Bristol-Myers Squibb

The compounds of the present disclosure may also be used as laboratoryreagents. Compounds may be instrumental in providing research tools fordesigning of viral replication assays, validation of animal assaysystems and structural biology studies to further enhance knowledge ofthe HCV disease mechanisms. Further, the compounds of the presentdisclosure are useful in establishing or determining the binding site ofother antiviral compounds, for example, by competitive inhibition.

The compounds of this disclosure may also be used to treat or preventviral contamination of materials and therefore reduce the risk of viralinfection of laboratory or medical personnel or patients who come incontact with such materials, e.g., blood, tissue, surgical instrumentsand garments, laboratory instruments and garments, and blood collectionor transfusion apparatuses and materials.

This disclosure is intended to encompass compounds having formula (I)when prepared by synthetic processes or by metabolic processes includingthose occurring in the human or animal body (in vivo) or processesoccurring in vitro.

The abbreviations used in the present application, includingparticularly in the illustrative schemes and examples which follow, arewell-known to those skilled in the art. Some of the abbreviations usedare as follows: RT for room temperature or retention time (context willdictate); R_(t) for retention time; min for minutes; TFA fortrifluoroacetic acid; DMSO for dimethylsulfoxide; Ph for phenyl; THF fortetrahydrofuran; Et₂O for diethyl ether; Boc or BOC fortert-butoxycarbonyl; MeOH for methanol; Et for ethyl; DMF fordimethylformamide; h or hr for hours; TBDPS for tert-butyldiphenylsilyl;DMAP for N,N-dimethylaminopyridine; TBAF for tetrabutylammoniumfluoride; Et₃N or TEA for triethylamine; HATU forO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate; Ac for acetate or acetyl; SEM for2-trimethylsilylethoxymethoxy; EDC or EDCI for1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; EEDQ forN-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline; MeOH for methanol; i-Bufor isobutyl; Bn for benzyl; and Me for methyl.

The compounds and processes of the present disclosure will be betterunderstood in connection with the following synthetic schemes whichillustrate the methods by which the compounds of the present disclosuremay be prepared. Starting materials can be obtained from commercialsources or prepared by well-established literature methods known tothose of ordinary skill in the art. It will be readily apparent to oneof ordinary skill in the art that the compounds defined above can besynthesized by substitution of the appropriate reactants and agents inthe syntheses shown below. It will also be readily apparent to oneskilled in the art that the selective protection and deprotection steps,as well as the order of the steps themselves, can be carried out invarying order, depending on the nature of the variables to successfullycomplete the syntheses below. The variables are as defined above unlessotherwise noted below.

Scheme 1: Substituted Phenylglycine Derivatives

Substituted phenylglycine derivatives can be prepared by a number ofmethods shown below. Phenylglycine t-butyl ester can be reductivelyalkylated (pathyway A) with an appropriate aldehyde and a reductant suchas sodium cyanoborohydride in acidic medium. Hydrolysis of the t-butylester can be accomplished with strong acid such as HCl ortrifluoroacetic acid. Alternatively, phenylglycine can be alkylated withan alkyl halide such as ethyl iodide and a base such as sodiumbicarbonate or potassium carbonate (pathway B). Pathway C illustratesreductive alkylation of phenylglycine as in pathway A followed by asecond reductive alkylation with an alternate aldehyde such asformaldehyde in the presence of a reducing agent and acid. Pathway Dillustrates the synthesis of substituted phenylglycines via thecorresponding mandelic acid analogs. Conversion of the secondary alcoholto a competent leaving group can be accomplished with p-toluensulfonylchloride. Displacement of the tosylate group with an appropriate aminefollowed by reductive removal of the benzyl ester can providesubstituted phenylglycine derivatives. In pathway E a racemicsubstituted phenylglycine derivative is resolved by esterification withan enantiomerically pure chiral auxiliary such as but not limited to(+)-1-phenylethanol, (−)-1-phenylethanol, an Evan's oxazolidinone, orenantiomerically pure pantolactone. Separation of the diastereomers isaccomplished via chromatography (silica gel, HPLC, crystallization, etc)followed by removal of the chiral auxiliary providing enantiomericallypure phenylglycine derivatives. Pathway H illustrates a syntheticsequence which intersects with pathway E wherein the aforementionedchiral auxiliary is installed prior to amine addition. Alternatively, anester of an arylacetic acid can be brominated with a source of bromoniumion such as bromine, N-bromosuccinimide, or CBr₄. The resultant benzylicbromide can be displaced with a variety of mono- or disubstituted aminesin the presence of a tertiary amine base such as triethylamine orHunig's base. Hydrolysis of the methyl ester via treatment with lithiumhydroxide at low temperature or 6N HCl at elevated temperature providesthe substituted phenylglycine derivatives. Another method is shown inpathway G. Glycine analogs can be derivatized with a variety of arylhalides in the presence of a source of palladium (0) such as palladiumbis(tributylphosphine) and base such as potassium phosphate. Theresultant ester can then be hydrolyzed by treatment with base or acid.It should be understood that other well known methods to preparephenylglycine derivatives exist in the art and can be amended to providethe desired compounds in this description. It should also be understoodthat the final phenylglycine derivatives can be purified to enantiomericpurity greater than 98% ee via preparative HPLC.

In another embodiment of the present disclosure, acylated phenylglycinederivatives may be prepared as illustrated below. Phenylglycinederivatives wherein the carboxylic acid is protected as an easilyremoved ester, may be acylated with an acid chloride in the presence ofa base such as triethylamine to provide the corresponding amides(pathway A). Pathway B illustrates the acylation of the startingphenylglycine derivative with an appropriate chloroformate while pathwayC shows reaction with an appropriate isocyanate or carbamoyl chloride.Each of the three intermediates shown in pathways A-C may be deprotectedby methods known by those skilled in the art (ie; treatment of thet-butyl ester with strong base such as HCl or trifluoroacetic acid).

Amino-substituted phenylacetic acids may be prepared by treatment of achloromethylphenylacetic acid with an excess of an amine.

Synthesis of Common Caps Compound Analysis Conditions:

Purity assessment and low resolution mass analysis were conducted on aShimadzu LC system coupled with Waters Micromass ZQ MS system. It shouldbe noted that retention times may vary slightly between machines.Additional LC conditions applicable to the current section, unless notedotherwise.

Cond.-MS-W1 Column=XTERRA 3.0×50 mm S7 Start % B=0 Final % B=100

Gradient time=2 minStop time=3 minFlow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-MS-W2 Column=XTERRA 3.0×50 mm S7 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-MS-W5 Column ═XTERRA 3.0×50 mm S7 Start % B=0 Final % B=30

Gradient time=2 minStop time=3 minFlow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-D1 Column=XTERRA C18 3.0×50 mm S7 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-D2 Column=Phenomenex-Luna 4.6×50 mm S10 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-MD1 Column=XTERRA 4.6×50 mm S5 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cond.-M3 Column=XTERRA C18 3.0×50 mm S7 Start % B=0 Final % B=40

Gradient time=2 minStop time=3 minFlow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Condition OL1 Column=Phenomenex-Luna 3.0×50 mm S10 Start % B=0 Final %B=100

Gradient time=4 minStop time=5 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Condition OL2 Column=Phenomenex-Luna 50×2 mm 3 u Start % B=0 Final %B=100

Gradient time=4 minStop time=5 minFlow Rate=0.8 mL/min

Oven Temp=40° C. Wavelength=220 nm Solvent A=0.1% TFA in 10%Acetonitrile/90% H₂O Solvent B=0.1% TFA in 90% Acetonitrile/10% H₂OCondition I Column=Phenomenex-Luna 3.0×50 mm S10 Start % B=0 Final %B=100

Gradient time=2 minStop time=3 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Condition II Column=Phenomenex-Luna 4.6×50 mm S10 Start % B=0 Final %B=100

Gradient time=2 minStop time=3 minFlow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Condition III Column=XTERRA C18 3.0×50 mm S7 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% H₂OSolvent B=0.1% TFA in 90% methanol/10% H₂O

Cap-1

A suspension of 10% Pd/C (2.0 g) in methanol (10 mL) was added to amixture of (R)-2-phenylglycine (10 g, 66.2 mmol), formaldehyde (33 mL of37% wt. in water), 1N HCl (30 mL) and methanol (30 mL), and exposed toH₂ (60 psi) for 3 hours. The reaction mixture was filtered throughdiatomaceous earth (Celite®), and the filtrate was concentrated invacuo. The resulting crude material was recrystallized from isopropanolto provide the HCl salt of Cap-1 as a white needle (4.0 g). Opticalrotation: −117.1° [c=9.95 mg/mL in H₂O; λ=589 nm]. ¹H NMR (DMSO-d₆,δ=2.5 ppm, 500 MHz): δ 7.43-7.34 (m, 5H), 4.14 (s, 1H), 2.43 (s, 6H); LC(Cond. I): RT=0.25; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂ 180.10.found 180.17; HRMS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂ 180.1025. found180.1017.

Cap-2

NaBH₃CN (6.22 g, 94 mmol) was added in portions over a few minutes to acooled (ice/water) mixture of (R)-2-Phenylglycine (6.02 g, 39.8 mmol)and methanol (100 mL), and stirred for 5 minutes. Acetaldehyde (10 mL)was added dropwise over 10 minutes and stirring was continued at thesame cooled temperature for 45 minutes and at ambient temperature for˜6.5 hours. The reaction mixture was cooled back with ice-water bath,treated with water (3 mL) and then quenched with a dropwise addition ofconcentrated HCl over ˜45 minutes until the pH of the mixture was˜1.5-2.0. The cooling bath was removed and the stirring was continuedwhile adding concentrated HCl in order to maintain the pH of the mixturearound 1.5-2.0. The reaction mixture was stirred overnight, filtered toremove the white suspension, and the filtrate was concentrated in vacuo.The crude material was recrystallized from ethanol to afford the HClsalt of Cap-2 as a shining white solid in two crops (crop-1: 4.16 g;crop-2: 2.19 g). ¹H NMR (DMSO-d₆, &2.5 ppm, 400 MHz): 10.44 (1.00, br s,1H), 7.66 (m, 2H), 7.51 (m, 3H), 5.30 (s, 1H), 3.15 (br m, 2H), 2.98 (brm, 2H), 1.20 (app br s, 6H). Crop-1: [α]²⁵ −102.21° (c=0.357, H₂O);crop-2: [α]²⁵-99.7° (c=0.357, H₂O). LC (Cond. I): RT=0.43 min; LC/MS:Anal. Calcd. for [M+H]⁺ C₁₂H₁₈NO₂: 208.13. found 208.26.

Cap-3

Acetaldehyde (5.0 mL, 89.1 mmol) and a suspension of 10% Pd/C (720 mg)in methanol/H₂O (4 mL/1 mL) was sequentially added to a cooled (˜15° C.)mixture of (R)-2-phenylglycine (3.096 g, 20.48 mmol), 1N HCl (30 mL) andmethanol (40 mL). The cooling bath was removed and the reaction mixturewas stirred under a balloon of H₂ for 17 hours. An additionalacetaldehyde (10 mL, 178.2 mmol) was added and stirring continued underH₂ atmosphere for 24 hours [Note: the supply of H₂ was replenished asneeded throughout the reaction]. The reaction mixture was filteredthrough diatomaceous earth) (Celite®, and the filtrate was concentratedin vacuo. The resulting crude material was recrystallized fromisopropanol to provide the HCl salt of (R)-2-(ethylamino)-2-phenylaceticacid as a shining white solid (2.846 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400MHz): δ 14.15 (br s, 1H), 9.55 (br s, 2H), 7.55-7.48 (m, 5H), 2.88 (brm, 1H), 2.73 (br m, 1H), 1.20 (app t, J=7.2, 3H). LC (Cond. I): R T=0.39min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₀H₁₄NO₂:180.10. found 180.18.

A suspension of 10% Pd/C (536 mg) in methanol/H₂O (3 mL/1 mL) was addedto a mixture of (R)-2-(ethylamino)-2-phenylacetic acid/HCl (1.492 g,6.918 mmol), formaldehyde (20 mL of 37% wt. in water), 1N HCl (20 mL)and methanol (23 mL). The reaction mixture was stirred under a balloonof H₂ for ˜72 hours, where the H₂ supply was replenished as needed. Thereaction mixture was filtered through diatomaceous earth (Celite®) andthe filtrate was concentrated in vacuo. The resulting crude material wasrecrystallized from isopropanol (50 mL) to provide the HCl salt of Cap-3as a white solid (985 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 10.48(br s, 1H), 7.59-7.51 (m, 5H), 5.26 (s, 1H), 3.08 (app br s, 2H), 2.65(br s, 3H), 1.24 (br m, 3H). LC (Cond. I): RT=0.39 min; >95% homogeneityindex; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂: 194.12. found 194.18;HRMS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂: 194.1180. found 194.1181.

Cap-4

ClCO₂Me (3.2 mL, 41.4 mmol) was added dropwise to a cooled (ice/water)THF (410 mL) semi-solution of (R)-tert-butyl 2-amino-2-phenylacetate/HCl(9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol)over 6 min, and stirred at similar temperature for 5.5 hours. Thevolatile component was removed in vacuo, and the residue was partitionedbetween water (100 mL) and ethyl acetate (200 mL). The organic layer waswashed with 1N HCl (25 mL) and saturated NaHCO₃ solution (30 mL), dried(MgSO₄), filtered, and concentrated in vacuo. The resultant colorlessoil was triturated from hexanes, filtered and washed with hexanes (100mL) to provide (R)-tert-butyl 2-(methoxycarbonylamino)-2-phenylacetateas a white solid (7.7 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 7.98 (d,J=8.0, 1H), 7.37-7.29 (m, 5H), 5.09 (d, J=8, 1H), 3.56 (s, 3H), 1.33 (s,9H). LC (Cond. I): RT=1.53 min; ˜90% homogeneity index; LC/MS: Anal.Calcd. for [M+Na]⁺ C₁₄H₁₉NNaO₄: 288.12. found 288.15.

TFA (16 mL) was added dropwise to a cooled (ice/water) CH₂Cl₂ (160 mL)solution of the above product over 7 minutes, and the cooling bath wasremoved and the reaction mixture was stirred for 20 hours. Since thedeprotection was still not complete, an additional TFA (1.0 mL) wasadded and stirring continued for an additional 2 hours. The volatilecomponent was removed in vacuo, and the resulting oil residue wastreated with diethyl ether (15 mL) and hexanes (12 mL) to provide aprecipitate. The precipitate was filtered and washed with diethylether/hexanes (˜1:3 ratio; 30 mL) and dried in vacuo to provide Cap-4 asa fluffy white solid (5.57 g). Optical rotation: −176.9° [c=3.7 mg/mL inH₂O; λ=589 nm]. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.84 (br s,1H), 7.96 (d, J=8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J=8.3, 1H), 3.55(s, 3H). LC (Cond. I): RT=1.01 min; >95% homogeneity index; LC/MS: Anal.Calcd. for [M+H]⁺ C₁₀H₁₂NO₄ 210.08. found 210.17; HRMS: Anal. Calcd. for[M+H]⁺ C₁₀H₁₂NO₄ 210.0766. found 210.0756.

Cap-5

A mixture of (R)-2-phenylglycine (1.0 g, 6.62 mmol), 1,4-dibromobutane(1.57 g, 7.27 mmol) and Na₂CO₃ (2.10 g, 19.8 mmol) in ethanol (40 mL)was heated at 100° C. for 21 hours. The reaction mixture was cooled toambient temperature and filtered, and the filtrate was concentrated invacuo. The residue was dissolved in ethanol and acidified with 1N HCl topH 3-4, and the volatile component was removed in vacuo. The resultingcrude material was purified by a reverse phase HPLC (water/methanol/TFA)to provide the TFA salt of Cap-5 as a semi-viscous white foam (1.0 g).¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 10.68 (br s, 1H), 7.51 (m, 5H), 5.23(s, 1H), 3.34 (app br s, 2H), 3.05 (app br s, 2H), 1.95 (app br s, 4H);RT=0.30 minutes (Cond. I); >98% homogeneity index; LC/MS: Anal. Calcd.for [M+H]⁺ C₁₂H₁₆NO₂: 206.12. found 206.25.

Cap-6

The TFA salt of Cap-6 was synthesized from (R)-2-phenylglycine and1-bromo-2-(2-bromoethoxy)ethane by using the method of preparation ofCap-5. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 12.20 (br s, 1H), 7.50 (m,5H), 4.92 (s, 1H), 3.78 (app br s, 4H), 3.08 (app br s, 2H), 2.81 (appbr s, 2H); RT=0.32 minutes (Cond. I); >98%; LC/MS: Anal. Calcd. for[M+H]⁺ C₁₂H₁₆NO₃: 222.11. found 222.20; HRMS: Anal. Calcd. for [M+H]⁺C₁₂H₁₆NO₃: 222.1130. found 222.1121.

Cap-7

A CH₂Cl₂ (200 mL) solution of p-toluenesulfonyl chloride (8.65 g, 45.4mmol) was added dropwise to a cooled (−5° C.) CH₂Cl₂ (200 mL) solutionof (S)-benzyl 2-hydroxy-2-phenylacetate (10.0 g, 41.3 mmol),triethylamine (5.75 mL, 41.3 mmol) and 4-dimethylaminopyridine (0.504 g,4.13 mmol), while maintaining the temperature between −5° C. and 0° C.The reaction was stirred at 0° C. for 9 hours, and then stored in afreezer (−25° C.) for 14 hours. It was allowed to thaw to ambienttemperature and washed with water (200 mL), 1N HCl (100 mL) and brine(100 mL), dried (MgSO₄), filtered, and concentrated in vacuo to providebenzyl 2-phenyl-2-(tosyloxy)acetate as a viscous oil which solidifiedupon standing (16.5 g). The chiral integrity of the product was notchecked and that product was used for the next step without furtherpurification. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 7.78 (d, J=8.6, 2H),7.43-7.29 (m, 10H), 7.20 (m, 2H), 6.12 (s, 1H), 5.16 (d, J=12.5, 1H),5.10 (d, J=12.5, 1H), 2.39 (s, 3H). RT=3.00 (Cond. III); >90%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₂₂H₂₀NaO₅S: 419.09.found 419.04.

A THF (75 mL) solution of benzyl 2-phenyl-2-(tosyloxy)acetate (6.0 g,15.1 mmol), 1-methylpiperazine (3.36 mL, 30.3 mmol) andN,N-diisopropylethylamine (13.2 mL, 75.8 mmol) was heated at 65° C. for7 hours. The reaction was allowed to cool to ambient temperature and thevolatile component was removed in vacuo. The residue was partitionedbetween ethylacetate and water, and the organic layer was washed withwater and brine, dried (MgSO₄), filtered, and concentrated in vacuo. Theresulting crude material was purified by flash chromatography (silicagel, ethyl acetate) to provide benzyl2-(4-methylpiperazin-1-yl)-2-phenylacetate as an orangish-brown viscousoil (4.56 g). Chiral HPLC analysis (Chiralcel OD-H) indicated that thesample is a mixture of enantiomers in a 38.2 to 58.7 ratio. Theseparation of the enantiomers were effected as follow: the product wasdissolved in 120 mL of ethanol/heptane (1:1) and injected (5mL/injection) on chiral HPLC column (Chiracel OJ, 5 cm ID×50 cm L, 20μm) eluting with 85:15 Heptane/ethanol at 75 mL/min, and monitored at220 nm. Enantiomer-1 (1.474 g) and enantiomer-2 (2.2149 g) wereretrieved as viscous oil. ¹H NMR (CDCl₃, δ=7.26, 500 MHz) 7.44-7.40 (m,2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), 5.13 (d, J=12.5, 1H), 5.08(d, J=12.5, 1H), 4.02 (s, 1H), 2.65-2.38 (app br s, 8H), 2.25 (s, 3H).RT=2.10 (Cond. III); >98% homogeneity index; LC/MS: Anal. Calcd. for[M+H]⁺ C₂₀H₂₅N₂O₂: 325.19. found 325.20.

A methanol (10 mL) solution of either enantiomer of benzyl2-(4-methylpiperazin-1-yl)-2-phenylacetate (1.0 g, 3.1 mmol) was addedto a suspension of 10% Pd/C (120 mg) in methanol (5.0 mL). The reactionmixture was exposed to a balloon of hydrogen, under a carefulmonitoring, for <50 minutes. Immediately after the completion of thereaction, the catalyst was filtered through diatomaceous earth (Celite®)and the filtrate was concentrated in vacuo to provide Cap-7,contaminated with phenylacetic acid as a tan foam (867.6 mg; mass isabove the theoretical yield). The product was used for the next stepwithout further purification. ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ7.44-7.37 (m, 2H), 7.37-7.24 (m, 3H), 3.92 (s, 1H), 2.63-2.48 (app. brs, 2H), 2.48-2.32 (m, 6H), 2.19 (s, 3H); RT=0.31 (Cond. II); >90%homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₉N₂O₂: 235.14.found 235.15; HRMS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₉N₂O₂: 235.1447. found235.1440.

The synthesis of Cap-8 and Cap-9 was conducted according to thesynthesis of Cap-7 by using appropriate amines for the SN₂ displacementstep (i.e., 4-hydroxypiperidine for Cap-8 and (S)-3-fluoropyrrolidinefor Cap-9) and modified conditions for the separation of the respectivestereoisomeric intermediates, as described below.

Cap-8

The enantiomeric separation of the intermediate benzyl2-(4-hydroxypiperidin-1-yl)-2-phenyl acetate was effected by employingthe following conditions: the compound (500 mg) was dissolved inethanol/heptane (5 mL/45 mL). The resulting solution was injected (5mL/injection) on a chiral HPLC column (Chiracel OJ, 2 cm ID×25 cm L, 10μm) eluting with 80:20 heptane/ethanol at 10 mL/min, monitored at 220nm, to provide 186.3 mg of enantiomer-1 and 209.1 mg of enantiomer-2 aslight-yellow viscous oils. These benzyl ester was hydrogenolysedaccording to the preparation of Cap-7 to provide Cap-8: ¹H NMR (DMSO-d₆,δ=2.5, 500 MHz) 7.40 (d, J=7, 2H), 7.28-7.20 (m, 3H), 3.78 (s 1H), 3.46(m, 1H), 2.93 (m, 1H), 2.62 (m, 1H), 2.20 (m, 2H), 1.70 (m, 2H), 1.42(m, 2H). RT=0.28 (Cond. II); >98% homogeneity index; LC/MS: Anal. Calcd.for [M+H]⁺ C₁₃H₁₈NO₃: 236.13. found 236.07; HRMS: Calcd. for [M+H]⁺C₁₃H₁₈NO₃: 236.1287. found 236.1283.

Cap-9

The diastereomeric separation of the intermediate benzyl2-((S)-3-fluoropyrrolidin-1-yl)-2-phenylacetate was effected byemploying the following conditions: the ester (220 mg) was separated ona chiral HPLC column (Chiracel OJ-H, 0.46 cm ID×25 cm L, 5 μm) elutingwith 95% CO₂/5% methanol with 0.1% TFA, at 10 bar pressure, 70 mL/minflow rate, and a temperature of 35° C. The HPLC elute for the respectivestereiosmers was concentrated, and the residue was dissolved in CH₂Cl₂(20 mL) and washed with an aqueous medium (10 mL water+1 mL saturatedNaHCO₃ solution). The organic phase was dried (MgSO₄), filtered, andconcentrated in vacuo to provide 92.5 mg of fraction-1 and 59.6 mg offraction-2. These benzyl esters were hydrogenolysed according to thepreparation of Cap-7 to prepare Caps 9a and 9b. Cap-9a (diastereomer-1;the sample is a TFA salt as a result of purification on a reverse phaseHPLC using H₂O/methanol/TFA solvent): ¹H NMR

(DMSO-d₆, δ=2.5, 400 MHz) 7.55-7.48 (m, 5H), 5.38 (d of m, J=53.7, 1H),5.09 (br s, 1H), 3.84-2.82 (br m, 4H), 2.31-2.09 (m, 2H). RT=0.42 (Cond.I); >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₅FNO₂:224.11. found 224.14; Cap-9b (diastereomer-2): ¹H NMR (DMSO-d₆, δ=2.5,400 MHz) 7.43-7.21 (m, 5H), 5.19 (d of m, J=55.9, 1H), 3.97 (s, 1H),2.95-2.43 (m, 4H), 2.19-1.78 (m, 2H). RT=0.44 (Cond. I); LC/MS: Anal.Calcd. for [M+H]⁺ C₁₂H₁₅FNO₂: 224.11. found 224.14.

Cap-10

To a solution of D-proline (2.0 g, 17 mmol) and formaldehyde (2.0 mL of37% wt. in H₂O) in methanol (15 mL) was added a suspension of 10% Pd/C(500 mg) in methanol (5 mL). The mixture was stirred under a balloon ofhydrogen for 23 hours. The reaction mixture was filtered throughdiatomaceous earth (Celite®) and concentrated in vacuo to provide Cap-10as an off-white solid (2.15 g). ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) 3.42(m, 1H), 3.37 (dd, J=9.4, 6.1, 1H), 2.85-2.78 (m, 1H), 2.66 (s, 3H),2.21-2.13 (m, 1H), 1.93-1.84 (m, 2H), 1.75-1.66 (m, 1H). RT=0.28 (Cond.II); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₆H₁₂NO₂:130.09. found 129.96.

Cap-11

A mixture of (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (0.50 g, 3.8mmol), formaldehyde (0.5 mL of 37% wt. in H₂O), 12 N HCl (0.25 mL) and10% Pd/C (50 mg) in methanol (20 mL) was stirred under a balloon ofhydrogen for 19 hours. The reaction mixture was filtered throughdiatomaceous earth (Celite®) and the filtrate was concentrated in vacuo.The residue was recrystallized from isopropanol to provide the HCl saltof Cap-11 as a white solid (337.7 mg). ¹H NMR (DMSO-d₆, δ=2.5, 500 MHz)5.39 (d m, J=53.7, 1H), 4.30 (m, 1H), 3.90 (ddd, J=31.5, 13.5, 4.5, 1H),3.33 (dd, J=25.6, 13.4, 1H), 2.85 (s, 3H), 2.60-2.51 (m, 1H), 2.39-2.26(m, 1H). RT=0.28 (Cond. II); >98% homogeneity index; LC/MS: Anal. Calcd.for [M+H]⁺ C₆H₁₁FNO₂: 148.08. found 148.06.

Cap-12 (Same as Cap 52)

L-Alanine (2.0 g, 22.5 mmol) was dissolved in 10% aqueous sodiumcarbonate solution (50 mL), and a THF (50 mL) solution of methylchloroformate (4.0 mL) was added to it. The reaction mixture was stirredunder ambient conditions for 4.5 hours and concentrated in vacuo. Theresulting white solid was dissolved in water and acidified with 1N HClto a pH˜2-3. The resulting solutions was extracted with ethyl acetate(3×100 mL), and the combined organic phase was dried (Na₂SO₄), filtered,and concentrated in vacuo to provide a colorless oil (2.58 g). 500 mg ofthis material was purified by a reverse phase HPLC (H₂O/methanol/TFA) toprovide 150 mg of Cap-12 as a colorless oil. ¹H NMR (DMSO-d₆, δ=2.5, 500MHz) 7.44 (d, J=7.3, 0.8H), 7.10 (br s, 0.2H), 3.97 (m, 1H), 3.53 (s,3H), 1.25 (d, J=7.3, 3H).

Cap-13

A mixture of L-alanine (2.5 g, 28 mmol), formaldehyde (8.4 g, 37 wt. %),1N HCl (30 mL) and 10% Pd/C (500 mg) in methanol (30 mL) was stirredunder a hydrogen atmosphere (50 psi) for 5 hours. The reaction mixturewas filtered through diatomaceous earth (Celite®) and the filtrate wasconcentrated in vacuo to provide the HCl salt of Cap-13 as an oil whichsolidified upon standing under vacuum (4.4 g; the mass is abovetheoretical yield). The product was used without further purification.¹H NMR (DMSO-d₆, δ=2.5, 500 MHz) δ 12.1 (br s, 1H), 4.06 (q, J=7.4, 1H),2.76 (s, 6H), 1.46 (d, J=7.3, 3H).

Cap-14

Step 1:

A mixture of (R)-(−)-D-phenylglycine tert-butyl ester (3.00 g, 12.3mmol), NaBH₃CN (0.773 g, 12.3 mmol), KOH (0.690 g, 12.3 mmol) and aceticacid (0.352 mL, 6.15 mmol) were stirred in methanol at 0° C. To thismixture was added glutaric dialdehyde (2.23 mL, 12.3 mmol) dropwise over5 minutes. The reaction mixture was stirred as it was allowed to warm toambient temperature and stirring was continued at the same temperaturefor 16 hours. The solvent was subsequently removed and the residue waspartitioned with 10% aqueous NaOH and ethyl acetate. The organic phasewas separated, dried (MgSO₄), filtered and concentrated to dryness toprovide a clear oil. This material was purified by reverse-phasepreparative HPLC (Primesphere C-18, 30×100 mm; CH₃CN—H₂O-0.1% TFA) togive the intermediate ester (2.70 g, 56%) as a clear oil. ¹H NMR (400MHz, CDCl₃) δ 7.53-7.44 (m, 3H), 7.40-7.37 (m, 2H), 3.87 (d, J=10.9 Hz,1H), 3.59 (d, J=10.9 Hz, 1H), 2.99 (t, J=11.2 Hz, 1H), 2.59 (t, J=11.4Hz, 1H), 2.07-2.02 (m, 2H), 1.82 (d, J=1.82 Hz, 3H), 1.40 (s, 9H).LC/MS: Anal. Calcd. for C₁₇H₂₅NO₂: 275. found: 276 (M+H)⁺.

Step 2:

To a stirred solution of the intermediate ester (1.12 g, 2.88 mmol) indichloromethane (10 mL) was added TFA (3 mL). The reaction mixture wasstirred at ambient temperature for 4 hours and then it was concentratedto dryness to give a light yellow oil. The oil was purified usingreverse-phase preparative HPLC (Primesphere C-18, 30×100 mm;CH₃CN—H₂O-0.1% TFA). The appropriate fractions were combined andconcentrated to dryness in vacuo. The residue was then dissolved in aminimum amount of methanol and applied to applied to MCX LP extractioncartridges (2×6 g). The cartridges were rinsed with methanol (40 mL) andthen the desired compound was eluted using 2M ammonia in methanol (50mL). Product-containing fractions were combined and concentrated and theresidue was taken up in water. Lyophilization of this solution providedthe title compound (0.492 g, 78%) as a light yellow solid. ¹H NMR(DMSO-d₆) δ 7.50 (s, 5H), 5.13 (s, 1H), 3.09 (br s, 2H), 2.92-2.89 (m,2H), 1.74 (m, 4H), 1.48 (br s, 2H). LC/MS: Anal. Calcd. for C₁₃H₁₇NO₂:219. found: 220 (M+H)⁺.

Cap-15

Step 1:

(S)-1-Phenylethyl 2-bromo-2-phenylacetate: To a mixture ofα-bromophenylacetic acid (10.75 g, 0.050 mol), (S)-(−)-1-phenylethanol(7.94 g, 0.065 mol) and DMAP (0.61 g, 5.0 mmol) in dry dichloromethane(100 mL) was added solid EDCI (12.46 g, 0.065 mol) all at once. Theresulting solution was stirred at room temperature under Ar for 18 hoursand then it was diluted with ethyl acetate, washed (H₂O×2, brine), dried(Na₂SO₄), filtered, and concentrated to give a pale yellow oil. Flashchromatography (SiO₂/hexane-ethyl acetate, 4:1) of this oil provided thetitle compound (11.64 g, 73%) as a white solid. ¹H NMR (400 MHz, CDCl₃)δ 7.53-7.17 (m, 10H), 5.95 (q, J=6.6 Hz, 0.5H), 5.94 (q, J=6.6 Hz,0.5H), 5.41 (s, 0.5H), 5.39 (s, 0.5H), 1.58 (d, J=6.6 Hz, 1.5H), 1.51(d, J=6.6 Hz, 1.5H).

Step 2:

(S)-1-Phenylethyl(R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate: To a solutionof (S)-1-phenylethyl 2-bromo-2-phenylacetate (0.464 g, 1.45 mmol) in THF(8 mL) was added triethylamine (0.61 mL, 4.35 mmol), followed bytetrabutylammonium iodide (0.215 g, 0.58 mmol). The reaction mixture wasstirred at room temperature for 5 minutes and then a solution of4-methyl-4-hydroxypiperidine (0.251 g, 2.18 mmol) in THF (2 mL) wasadded. The mixture was stirred for 1 hour at room temperature and thenit was heated at 55-60° C. (oil bath temperature) for 4 hours. Thecooled reaction mixture was then diluted with ethyl acetate (30 mL),washed (H₂O×2, brine), dried (MgSO₄), filtered and concentrated. Theresidue was purified by silica gel chromatography (0-60% ethylacetate-hexane) to provide first the (S,R)-isomer of the title compound(0.306 g, 60%) as a white solid and then the corresponding (S,S)-isomer(0.120 g, 23%), also as a white solid. (S,R)-isomer: ¹H NMR (CD₃OD) δ7.51-7.45 (m, 2H), 7.41-7.25 (m, 8H), 5.85 (q, J=6.6 Hz, 1H), 4.05 (s,1H), 2.56-2.45 (m, 2H), 2.41-2.29 (m, 2H), 1.71-1.49 (m, 4H), 1.38 (d,J=6.6 Hz, 3H), 1.18 (s, 3H). LCMS: Anal. Calcd. for C₂₂H₂₇NO₃: 353.found: 354 (M+H)⁺. (S,S)-isomer: ¹H NMR (CD₃OD) δ 7.41-7.30 (m, 5H),7.20-7.14 (m, 3H), 7.06-7.00 (m, 2H), 5.85 (q, J=6.6 Hz, 1H), 4.06 (s,1H), 2.70-2.60 (m, 1H), 2.51 (dt, J=6.6, 3.3 Hz, 1H), 2.44-2.31 (m, 2H),1.75-1.65 (m, 1H), 1.65-1.54 (m, 3H), 1.50 (d, J=6.8 Hz, 3H), 1.20 (s,3H). LCMS: Anal. Calcd. for C₂₂H₂₇NO₃: 353. found: 354 (M+H)⁺.

Step 3:

(R)-2-(4-Hydroxy-4-methylpiperidin-1-yl)-2-phenylacetic acid: To asolution of (S)-1-phenylethyl(R)-2-(4-hydroxy-4-methylpiperidin-1-yl)-2-phenylacetate (0.185 g, 0.52mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL)and the mixture was stirred at room temperature for 2 hours. Thevolatiles were subsequently removed in vacuo and the residue waspurified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm;CH₃CN—H₂O-0.1% TFA) to give the title compound (as TFA salt) as a palebluish solid (0.128 g, 98%). LCMS: Anal. Calcd. for C₁₄H₁₉NO₃: 249.found: 250 (M+H)⁺.

Cap-16

Step 1:

(S)-1-Phenylethyl 2-(2-fluorophenyl)acetate: A mixture of2-fluorophenylacetic acid (5.45 g, 35.4 mmol), (S)-1-phenylethanol (5.62g, 46.0 mmol), EDCI (8.82 g, 46.0 mmol) and DMAP (0.561 g, 4.60 mmol) inCH₂Cl₂ (100 mL) was stirred at room temperature for 12 hours. Thesolvent was then concentrated and the residue partitioned with H₂O-ethylacetate. The phases were separated and the aqueous layer back-extractedwith ethyl acetate (2×). The combined organic phases were washed (H₂O,brine), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residuewas purified by silica gel chromatography (Biotage/0-20% ethylacetate-hexane) to provide the title compound as a colorless oil (8.38g, 92%). ¹H NMR (400 MHz, CD₃OD) δ 7.32-7.23 (m, 7H), 7.10-7.04 (m, 2),5.85 (q, J=6.5 Hz, 1H), 3.71 (s, 2H), 1.48 (d, J=6.5 Hz, 3H).

Step 2:

(R)-((S)-1-Phenylethyl) 2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate: Toa solution of (S)-1-phenylethyl 2-(2-fluorophenyl)acetate (5.00 g, 19.4mmol) in THF (1200 mL) at 0° C. was added DBU (6.19 g, 40.7 mmol) andthe solution was allowed to warm to room temperature while stirring for30 minutes. The solution was then cooled to −78° C. and a solution ofCBr₄ (13.5 g, 40.7 mmol) in THF (100 mL) was added and the mixture wasallowed to warm to −10° C. and stirred at this temperature for 2 hours.The reaction mixture was quenched with saturated aq. NH₄Cl and thelayers were separated. The aqueous layer was back-extracted with ethylacetate (2×) and the combined organic phases were washed (H₂O, brine),dried (Na₂SO₄), filtered, and concentrated in vacuo. To the residue wasadded piperidine (5.73 mL, 58.1 mmol) and the solution was stirred atroom temperature for 24 hours. The volatiles were then concentrated invacuo and the residue was purified by silica gel chromatography(Biotage/0-30% diethyl ether-hexane) to provide a pure mixture ofdiastereomers (2:1 ratio by ¹H NMR) as a yellow oil (2.07 g, 31%), alongwith unreacted starting material (2.53 g, 51%). Further chromatographyof the diastereomeric mixture (Biotage/0-10% diethyl ether-toluene)provided the title compound as a colorless oil (0.737 g, 11%). ¹H NMR(400 MHz, CD₃OD) δ 7.52 (ddd, J=9.4, 7.6, 1.8 Hz, 1H), 7.33-7.40 (m, 1),7.23-7.23 (m, 4H), 7.02-7.23 (m, 4H), 5.86 (q, J=6.6 Hz, 1H), 4.45 (s,1H), 2.39-2.45 (m, 4H), 1.52-1.58 (m, 4H), 1.40-1.42 (m, 1H), 1.38 (d,J=6.6 Hz, 3H). LCMS: Anal. Calcd. for C₂₁H₂₄FNO₂: 341. found: 342(M+H)⁺.

Step 3:

(R)-2-(2-fluorophenyl)-2-(piperidin-1-yl)acetic acid: A mixture of(R)-((S)-1-phenylethyl) 2-(2-fluorophenyl)-2-(piperidin-1-yl)acetate(0.737 g, 2.16 mmol) and 20% Pd(OH)₂/C (0.070 g) in ethanol (30 mL) washydrogenated at room temperature and atmospheric pressure (H₂ balloon)for 2 hours. The solution was then purged with Ar, filtered throughdiatomaceous earth (Celite®), and concentrated in vacuo. This providedthe title compound as a colorless solid (0.503 g, 98%). ¹H NMR (400 MHz,CD₃OD) δ 7.65 (ddd, J=9.1, 7.6, 1.5 Hz, 1H), 7.47-7.53 (m, 1H),7.21-7.30 (m, 2H), 3.07-3.13 (m, 4H), 1.84 (br s, 4H), 1.62 (br s, 2H).LCMS: Anal. Calcd. for C₁₃H₁₆FNO₂: 237. found: 238 (M+H)⁺.

Cap-17

Step 1:

(S)-1-Phenylethyl(R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate: To a solutionof (S)-1-phenylethyl 2-bromo-2-phenylacetate (1.50 g, 4.70 mmol) in THF(25 mL) was added triethylamine (1.31 mL, 9.42 mmol), followed bytetrabutylammonium iodide (0.347 g, 0.94 mmol). The reaction mixture wasstirred at room temperature for 5 minutes and then a solution of4-phenyl-4-hydroxypiperidine (1.00 g, 5.64 mmol) in THF (5 mL) wasadded. The mixture was stirred for 16 hours and then it was diluted withethyl acetate (100 mL), washed (H₂O×2, brine), dried (MgSO₄), filteredand concentrated. The residue was purified on a silica gel column (0-60%ethyl acetate-hexane) to provide an approximately 2:1 mixture ofdiastereomers, as judged by ¹H NMR. Separation of these isomers wasperformed using supercritical fluid chromatography (Chiralcel OJ-H,30×250 mm; 20% ethanol in CO₂ at 35° C.), to give first the (R)-isomerof the title compound (0.534 g, 27%) as a yellow oil and then thecorresponding (S)-isomer (0.271 g, 14%), also as a yellow oil.(S,R)-isomer: ¹H NMR (400 MHz, CD₃OD) δ 7.55-7.47 (m, 4H), 7.44-7.25 (m,10H), 7.25-7.17 (m, 1H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s, 1H), 2.82-2.72(m, 1H), 2.64 (dt, J=11.1, 2.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.40 (dt,J=11.1, 2.5 Hz, 1H), 2.20 (dt, J=12.1, 4.6 Hz, 1H), 2.10 (dt, J=12.1,4.6 Hz, 1H), 1.72-1.57 (m, 2H), 1.53 (d, J=6.5 Hz, 3H). LCMS: Anal.Calcd. for C₂₇H₂₉NO₃: 415. found: 416 (M+H)⁺; (S,S)-isomer: H¹NMR (400MHz, CD₃OD) δ 7.55-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.30 (m, 5H),7.25-7.13 (m, 4H), 7.08-7.00 (m, 2H), 5.88 (q, J=6.6 Hz, 1H), 4.12 (s,1H), 2.95-2.85 (m, 1H), 2.68 (dt, J=11.1, 2.5 Hz, 1H), 2.57-2.52 (m,1H), 2.42 (dt, J=11.1, 2.5 Hz, 1H), 2.25 (dt, J=12.1, 4.6 Hz, 1H), 2.12(dt, J=12.1, 4.6 Hz, 1H), 1.73 (dd, J=13.6, 3.0 Hz, 1H), 1.64 (dd,J=13.6, 3.0 Hz, 1H), 1.40 (d, J=6.6 Hz, 3H). LCMS: Anal. Calcd. forC₂₇H₂₉NO₃: 415. found: 416 (M+H)⁺.

The following esters were prepared in similar fashion:

Inter- mediate- 17a

Diastereomer 1: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.36 (d, J = 6.41 Hz,3H) 2.23-2.51 (m, 4H) 3.35 (s, 4H) 4.25 (s, 1H) 5.05 (s, 2H) 5.82 (d, J= 6.71 Hz, 1H) 7.15-7.52 (m, 15H). LCMS: Anal. Calcd. for: C₂₈H₃₀N₂O₄458.22; Found: 459.44 (M + H)⁺. Diastereomer 2: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.45 (d, J = 6.71 Hz, 3H) 2.27-2.44 (m, 4H) 3.39 (s, 4H)4.23 (s, 1H) 5.06 (s, 2H) 5.83 (d, J = 6.71 Hz, 1H) 7.12 (dd, J = 6.41,3.05 Hz, 2H) 7.19-7.27 (m, 3H) 7.27- 7.44 (m, 10H). LCMS: Anal. Calcd.for: C₂₈H₃₀N₂O₄ 458.22; Found: 459.44 (M + H)⁺. Inter- mediate- 17b

Diasteromer 1: RT = 11.76 minutes (Cond'n II); LCMS: Anal. Calcd. for:C₂₀H₂₂N₂O₃ 338.16 Found: 339.39 (M + H)⁺; Diastereomer 2: RT = 10.05minutes (Cond'n II); LCMS: Anal. Calcd. for: C₂₀H₂₂N₂O₃ 338.16; Found:339.39 (M + H)⁺. Inter- mediate- 17c

Diastereomer 1: T_(R) = 4.55 minutes (Cond'n I); LCMS: Anal. Calcd. for:C₂₁H₂₆N₂O₂ 338.20 Found: 339.45 (M + H)⁺; Diastereomer 2: T_(R) = 6.00minutes (Cond'n I); LCMS: Anal. Calcd. for: C₂₁H₂₆N₂O₂ 338.20 Found:339.45 (M + H)⁺. Inter- mediate- 17d

Diastereomer 1: RT = 7.19 minutes (Cond'n I); LCMS: Anal. Calcd. for:C₂₇H₂₉NO₂ 399.22 Found: 400.48 (M + H)⁺; Diastereomer 2: RT = 9.76minutes (Cond'n I); LCMS: Anal. Calcd. for: C₂₇H₂₉NO₂ 399.22 Found:400.48 (M + H)⁺.

Chiral SFC Conditions for Determining Retention Time Condition I Column:Chiralpak AD-H Column, 4.62×50 mm, 5 μm

Solvents: 90% CO2-10% methanol with 0.1% DEA

Temp: 35° C. Pressure: 150 bar

Flow rate: 2.0 mL/min.UV monitored @ 220 nmInjection: 1.0 mg/3 mL methanol

Condition II Column: Chiralcel OD-H Column, 4.62×50 mm, 5 μm

Solvents: 90% CO2-10% methanol with 0.1% DEA

Temp: 35° C. Pressure: 150 bar

Flow rate: 2.0 mL/min.UV monitored @ 220 nmInjection: 1.0 mg/mL methanol

Cap 17, Step 2; (R)-2-(4-Hydroxy-4-phenylpiperidin-1-yl)-2-phenylaceticacid: To a solution of (S)-1-phenylethyl(R)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-2-phenylacetate (0.350 g, 0.84mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL)and the mixture was stirred at room temperature for 2 hours. Thevolatiles were subsequently removed in vacuo and the residue waspurified by reverse-phase preparative HPLC (Primesphere C-18, 20×100 mm;CH₃CN—H₂O-0.1% TFA) to give the title compound (as TFA salt) as a whitesolid (0.230 g, 88%). LCMS: Anal. Calcd. for C₁₉H₂₁NO₃: 311.15. found:312 (M+H)⁺.

The following carboxylic acids were prepared in optically pure form in asimilar fashion:

Cap-17a

RT = 2.21 (Cond'n II); ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.20- 2.35 (m,2H) 2.34-2.47 (m, 2H) 3.37 (s, 4H) 3.71 (s, 1H) 5.06 (s, 2H) 7.06-7.53(m, 10H). LCMS: Anal. Calcd. for: C₂₀H₂₂N₂O₄ 354.16; Found: 355.38 (M +H)⁺. Cap-17b

RT = 0.27 (Cond'n III); LCMS: Anal. Calcd. for: C₁₂H₁₄N₂O₃ 234.10;Found: 235.22 (M + H)⁺. Cap-17c

RT = 0.48 (Cond'n II); LCMS: Anal. Calcd. for: C₁₃H₁₈N₂O₂ 234.14; Found:235.31 (M + H)⁺. Cap 17d

RT = 2.21 (Cond'n I); LCMS: Anal. Calcd. for: C₁₉H₂₁NO₂ 295.16; Found:296.33 (M + H)⁺.

LCMS Conditions for Determining Retention Time Condition I Column:Phenomenex-Luna 4.6×50 mm S10 Start % B=0 Final % B=100 Gradient Time=4min

Flow Rate=4 mL/min

Wavelength=220

Solvent A=10% methanol-90% H₂O-0.1% TFASolvent B=90% methanol-10% H₂O-0.1% TFA

Condition II Column: Waters-Sunfire 4.6×50 mm S5 Start % B=0 Final %B=100 Gradient Time=2 min

Flow Rate=4 mL/min

Wavelength=220

Solvent A=10% methanol-90% H₂O-0.1% TFASolvent B=90% methanol-10% H₂O-0.1% TFA

Condition III Column: Phenomenex 10μ 3.0×50 mm Start % B=0 Final % B=100Gradient Time=2 min

Flow Rate=4 mL/min

Wavelength=220

Solvent A=10% methanol-90% H₂O-0.1% TFASolvent B=90% methanol-10% H₂O-0.1% TFA

Step 1;

(R,S)-Ethyl 2-(4-pyridyl)-2-bromoacetate: To a solution of ethyl4-pyridylacetate (1.00 g, 6.05 mmol) in dry THF (150 mL) at 0° C. underargon was added DBU (0.99 mL, 6.66 mmol). The reaction mixture wasallowed to warm to room temperature over 30 minutes and then it wascooled to −78° C. To this mixture was added CBr₄ (2.21 g, 6.66 mmol) andstirring was continued at −78° C. for 2 hours. The reaction mixture wasthen quenched with sat. aq. NH₄Cl and the phases were separated. Theorganic phase was washed (brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The resulting yellow oil was immediately purifiedby flash chromatography (SiO₂/hexane-ethyl acetate, 1:1) to provide thetitle compound (1.40 g, 95%) as a somewhat unstable yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 8.62 (dd, J=4.6, 1.8 Hz, 2H), 7.45 (dd, J=4.6, 1.8Hz, 2H), 5.24 (s, 1H), 4.21-4.29 (m, 2H), 1.28 (t, J=7.1 Hz, 3H). LCMS:Anal. Calcd. for C₉H₁₀BrNO₂: 242, 244. found: 243, 245 (M+H)⁺.

Step 2;

(R,S)-Ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate: To a solution of(R,S)-ethyl 2-(4-pyridyl)-2-bromoacetate (1.40 g, 8.48 mmol) in DMF (10mL) at room temperature was added dimethylamine (2M in THF, 8.5 mL, 17.0mmol). After completion of the reaction (as judged by thin layerchromatography) the volatiles were removed in vacuo and the residue waspurified by flash chromatography (Biotage, 40+M SiO₂ column; 50%-100%ethyl acetate-hexane) to provide the title compound (0.539 g, 31%) as alight yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J=6.0 Hz, 2H), 7.36(d, J=6.0 Hz, 2H), 4.17 (m, 2H), 3.92 (s, 1H), 2.27 (s, 6H), 1.22 (t,J=7.0 Hz). LCMS: Anal. Calcd. for C₁₁H₁₆N₂O₂: 208. found: 209 (M+H)⁺.

Step 3;

(R,S)-2-(4-Pyridyl)-2-(N,N-dimethylamino)acetic acid: To a solution of(R,S)-ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate (0.200 g, 0.960mmol) in a mixture of THF-methanol-H₂O (1:1:1, 6 mL) was added powderedLiOH (0.120 g, 4.99 mmol) at room temperature. The solution was stirredfor 3 hours and then it was acidified to pH 6 using 1N HCl. The aqueousphase was washed with ethyl acetate and then it was lyophilized to givethe dihydrochloride of the title compound as a yellow solid (containingLiCl). The product was used as such in subsequent steps. ¹H NMR (400MHz, DMSO-d₆) δ 8.49 (d, J=5.7 Hz, 2H), 7.34 (d, J=5.7 Hz, 2H), 3.56 (s,1H), 2.21 (s, 6H).

The following examples were prepared in similar fashion using the methoddescribed above;

Cap-19

LCMS: Anal. Calcd. for C₉H₁₂N₂O₂: 180; found: 181 (M + H)⁺. Cap-20

LCMS: no ionization. ¹H NMR (400 MHz, CD₃OD) δ 8.55 (d, J = 4.3 Hz, 1H),7.84 (app t, J = 5.3 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.37 (app t, J =5.3 Hz), 1H), 4.35 (s, 1H), 2.60 (s, 6H). Cap-21

LCMS: Anal. Calcd. for C₉H₁₁ClN₂O₂: 214, 216; found: 215, 217 (M + H)⁺.Cap-22

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-23

LCMS: Anal. Calcd. for C₁₄H₁₅NO₂: 229; found: 230 (M + H)⁺. Cap-24

LCMS: Anal. Calcd. for C₁₁H₁₂F₃NO₂: 247; found: 248 (M + H)⁺. Cap-25

LCMS: Anal. Calcd. for C₁₁H₁₂F₃NO₂: 247; found: 248 (M + H)⁺. Cap-26

LCMS: Anal. Calcd. for C₁₀H₁₂FNO₂: 197; found: 198 (M + H)⁺. Cap-27

LCMS: Anal. Calcd. for C₁₀H₁₂FNO₂: 247; found: 248 (M + H)⁺. Cap-28

LCMS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213; found: 214 (M + H)⁺. Cap-29

LCMS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213; found: 214 (M + H)⁺. Cap-30

LCMS: Anal. Calcd. for C₁₀H₁₂ClNO₂: 213; found: 214 (M + H)⁺. Cap-31

LCMS: Anal. Calcd. for C₈H₁₂N₂O₂S: 200; found: 201 (M + H)⁺. Cap-32

LCMS: Anal. Calcd. for C₈H₁₁NO₂S: 185; found: 186 (M + H)⁺. Cap-33

LCMS: Anal. Calcd. for C₈H₁₁NO₂S: 185; found: 186 (M + H)⁺. Cap-34

LCMS: Anal. Calcd. for C₁₁H₁₂N₂O₃: 220; found: 221 (M + H)⁺. Cap-35

LCMS: Anal. Calcd. for C₁₂H₁₃NO₂S: 235; found: 236 (M + H)⁺. Cap-36

LCMS: Anal. Calcd. for C₁₂H₁₄N₂O₂S: 250; found: 251 (M + H)⁺.

Cap-37

Step 1;

(R,S)-Ethyl 2-(quinolin-3-yl)-2-(N,N-dimethylamino)-acetate: A mixtureof ethyl N,N-dimethylaminoacetate (0.462 g, 3.54 mmol), K₃PO₄ (1.90 g,8.95 mmol), Pd(t-Bu₃P)₂ (0.090 g, 0.176 mmol) and toluene (10 mL) wasdegassed with a stream of Ar bubbles for 15 minutes. The reactionmixture was then heated at 100° C. for 12 hours, after which it wascooled to room temperature and poured into H₂O. The mixture wasextracted with ethyl acetate (2×) and the combined organic phases werewashed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified first by reverse-phase preparative HPLC(Primesphere C-18, 30×100 mm; CH₃CN—H₂O-5 mM NH₄OAc) and then by flashchromatography (SiO₂/hexane-ethyl acetate, 1:1) to provide the titlecompound (0.128 g, 17%) as an orange oil. ¹H NMR (400 MHz, CDCl₃) δ 8.90(d, J=2.0 Hz, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.03-8.01 (m, 2H), 7.77 (ddd,J=8.3, 6.8, 1.5 Hz, 1H), 7.62 (ddd, J=8.3, 6.8, 1.5 Hz, 1H), 4.35 (s,1H), 4.13 (m, 2H), 2.22 (s, 6H), 1.15 (t, J=7.0 Hz, 3H). LCMS: Anal.Calcd. for C₁₅H₁₈N₂O₂: 258. found: 259 (M+H)⁺.

Step 2;

(R,S) 2-(Quinolin-3-yl)-2-(N,N-dimethylamino)acetic acid: A mixture of(R,S)-ethyl 2-(quinolin-3-yl)-2-(N,N-dimethylamino)acetate (0.122 g,0.472 mmol) and 6M HCl (3 mL) was heated at 100° C. for 12 hours. Thesolvent was removed in vacuo to provide the dihydrochloride of the titlecompound (0.169 g, >100%) as a light yellow foam. The unpurifiedmaterial was used in subsequent steps without further purification.LCMS: Anal. Calcd. for C₁₃H₁₄N₂O₂: 230. found: 231 (M+H)⁺.

Cap-38

Step 1;

(R)-((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetate and(S)-((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetate: Toa mixture of (RS)-2-(dimethylamino)-2-(2-fluorophenyl)acetic acid (2.60g, 13.19 mmol), DMAP (0.209 g, 1.71 mmol) and (S)-1-phenylethanol (2.09g, 17.15 mmol) in CH₂Cl₂ (40 mL) was added EDCI (3.29 g, 17.15 mmol) andthe mixture was allowed to stir at room temperature for 12 hours. Thesolvent was then removed in vacuo and the residue partitioned with ethylacetate-H₂O. The layers were separated, the aqueous layer wasback-extracted with ethyl acetate (2×) and the combined organic phaseswere washed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated invacuo. The residue was purified by silica gel chromatography(Biotage/0-50% diethyl ether-hexane). The resulting pure diastereomericmixture was then separated by reverse-phase preparative HPLC(Primesphere C-18, 30×100 mm; CH₃CN—H₂O-0.1% TFA) to give first(S)-1-phenethyl (R)-2-(dimethylamino)-2-(2-fluorophenyl)acetate (0.501g, 13%) and then (S)-1-phenethyl(S)-2-(dimethylamino)-2-(2-fluorophenyl)-acetate (0.727 g. 18%), both astheir TFA salts. (S,R)-isomer: ¹H NMR (400 MHz, CD₃OD) δ 7.65-7.70 (m,1H), 7.55-7.60 (ddd, J=9.4, 8.1, 1.5 Hz, 1H), 7.36-7.41 (m, 2H),7.28-7.34 (m, 5H), 6.04 (q, J=6.5 Hz, 1H), 5.60 (s, 1H), 2.84 (s, 6H),1.43 (d, J=6.5 Hz, 3H). LCMS: Anal. Calcd. for C₁₈H₂₀FNO₂: 301. found:302 (M+H)⁺; (S,S)-isomer: ¹H NMR (400 MHz, CD₃OD) δ 7.58-7.63 (m, 1H),7.18-7.31 (m, 6H), 7.00 (dd, J=8.5, 1.5 Hz, 2H), 6.02 (q, J=6.5 Hz, 1H),5.60 (s, 1H), 2.88 (s, 6H), 1.54 (d, J=6.5 Hz, 3H). LCMS: Anal. Calcd.for C₁₈H₂₀FNO₂: 301. found: 302 (M+H)⁺.

Step 2;

(R)-2-(dimethylamino)-2-(2-fluorophenyl)acetic acid: A mixture of(R)-((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetate TFAsalt (1.25 g, 3.01 mmol) and 20% Pd(OH)₂/C (0.125 g) in ethanol (30 mL)was hydrogenated at room temperature and atmospheric pressure (H₂balloon) for 4 hours. The solution was then purged with Ar, filteredthrough diatomaceous earth (Celite®), and concentrated in vacuo. Thisgave the title compound as a colorless solid (0.503 g, 98%). ¹H NMR (400MHz, CD₃OD) δ 7.53-7.63 (m, 2H), 7.33-7.38 (m, 2H), 5.36 (s, 1H), 2.86(s, 6H). LCMS: Anal. Calcd. for C₁₀H₁₂FNO₂: 197. found: 198 (M+H)⁺.

The S-isomer could be obtained from (S)-((S)-1-phenylethyl)2-(dimethylamino)-2-(2-fluorophenyl)acetate TFA salt in similar fashion.

Cap-39

A mixture of (R)-(2-chlorophenyl)glycine (0.300 g, 1.62 mmol),formaldehyde (35% aqueous solution, 0.80 mL, 3.23 mmol) and 20%Pd(OH)₂/C (0.050 g) was hydrogenated at room temperature and atmosphericpressure (H₂ balloon) for 4 hours. The solution was then purged with Ar,filtered through diatomaceous earth (Celite®) and concentrated in vacuo.The residue was purified by reverse-phase preparative HPLC (PrimesphereC-18, 30×100 mm; CH₃CN—H₂O-0.1% TFA) to give the TFA salt of the titlecompound (R)-2-(dimethylamino)-2-(2-chlorophenyl)acetic acid as acolorless oil (0.290 g, 55%). ¹H NMR (400 MHz, CD₃OD) δ 7.59-7.65 (m,2H), 7.45-7.53 (m, 2H), 5.40 (s, 1H), 2.87 (s, 6H). LCMS: Anal. Calcd.for C₁₀H₁₂ClNO₂: 213. found: 214 (M+H)⁺.

Cap-40

To an ice-cold solution of (R)-(2-chlorophenyl)glycine (1.00 g, 5.38mmol) and NaOH (0.862 g, 21.6 mmol) in H₂O (5.5 mL) was added methylchloroformate (1.00 mL, 13.5 mmol) dropwise. The mixture was allowed tostir at 0° C. for 1 hour and then it was acidified by the addition ofconc. HCl (2.5 mL). The mixture was extracted with ethyl acetate (2×)and the combined organic phase was washed (H₂O, brine), dried (Na₂SO₄),filtered, and concentrated in vacuo to give the title compound(R)-2-(methoxycarbonylamino)-2-(2-chlorophenyl)acetic acid as ayellow-orange foam (1.31 g, 96%). ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.43(m, 2H), 7.29-7.31 (m, 2H), 5.69 (s, 1H), 3.65 (s, 3H). LCMS: Anal.Calcd. for C₁₀H₁₀ClNO₄: 243. found: 244 (M+H)⁺.

Cap-41

To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and thesolution was stirred at room temperature for 3 hours. The reactionmixture was then diluted with ethyl acetate and extracted with H₂O (2×).The aqueous phase was lyophilized and the residue was purified by silicagel chromatography (Biotage/0-10% methanol-CH₂Cl₂) to give the titlecompound 2-(2-(Morpholinomethyl)phenyl)acetic acid as a colorless solid(2.22 g, 87%). ¹H NMR (400 MHz, CD₃OD) δ 7.37-7.44 (m, 3H), 7.29-7.33(m, 1H), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H).LCMS: Anal. Calcd. for C₁₃H₁₇NO₃: 235. found: 236 (M+H)⁺.

The following examples were similarly prepared using the methoddescribed for Cap-41:

Cap-42

LCMS: Anal. Calcd. for C₁₄H₁₉NO₂: 233; found: 234 (M + H)⁺. Cap-43

LCMS: Anal. Calcd. for C₁₃H₁₇NO₂: 219; found: 220 (M + H)⁺. Cap-44

LCMS: Anal. Calcd. for C₁₁H₁₅NO₂: 193; found: 194 (M + H)⁺. Cap-45

LCMS: Anal. Calcd. for C₁₄H₂₀N₂O₂: 248; found: 249 (M + H)⁺.

Cap-45a

HMDS (1.85 mL, 8.77 mmol) was added to a suspension of(R)-2-amino-2-phenylacetic acid p-toluenesulfonate (2.83 g, 8.77 mmol)in CH₂Cl₂ (10 mL) and the mixture was stirred at room temperature for 30minutes. Methyl isocyanate (0.5 g, 8.77 mmol) was added in one portionstirring continued for 30 minutes. The reaction was quenched by additionof H₂O (5 mL) and the resulting precipitate was filtered, washed withH₂O and n-hexanes, and dried under vacuum.(R)-2-(3-methylureido)-2-phenylacetic acid (1.5 g; 82%) was recovered asa white solid and it was used without further purification. ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.54 (d, J=4.88 Hz, 3H) 5.17 (d, J=7.93 Hz, 1H) 5.95(q, J=4.48 Hz, 1H) 6.66 (d, J=7.93 Hz, 1H) 7.26-7.38 (m, 5H) 12.67 (s,1H). LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₃ 208.08 found 209.121 (M+H)⁺; HPLCPhenomenex C-18 3.0×46 mm, 0 to 100% B over 2 minutes, 1 minute holdtime, A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol,0.1% TFA, RT=1.38 min, 90% homogeneity index.

Cap-46

The desired product was prepared according to the method described forCap-45a. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.96 (t, J=7.17 Hz, 3H)2.94-3.05 (m, 2H) 5.17 (d, J=7.93 Hz, 1H) 6.05 (t, J=5.19 Hz, 1H) 6.60(d, J=7.63 Hz, 1H) 7.26-7.38 (m, 5H) 12.68 (s, 1H). LCMS: Anal. Calcd.for C₁₁H₁₄N₂O₃ 222.10 found 223.15 (M+H)⁺. HPLC XTERRA C-18 3.0×506 mm,0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10%methanol, 0.2% H₃PO₄, B=10% water, 90% methanol, 0.2% H₃PO₄, RT=0.87min, 90% homogeneity index.

Cap-47

Step 1;

(R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate: To a stirredsolution of (R)-tert-butyl-2-amino-2-phenylacetate (1.0 g, 4.10 mmol)and Hunig's base (1.79 mL, 10.25 mmol) in DMF (40 mL) was addeddimethylcarbamoyl chloride (0.38 mL, 4.18 mmol) dropwise over 10minutes. After stirring at room temperature for 3 hours, the reactionwas concentrated under reduced pressure and the resulting residue wasdissolved in ethyl acetate. The organic layer was washed with H₂O, 1Naq. HCl and brine, dried (MgSO₄), filtered and concentrated underreduced pressure. (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetatewas obtained as a white solid (0.86 g; 75%) and used without furtherpurification. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 2.82 (s, 6H)5.17 (d, J=7.63 Hz, 1H) 6.55 (d, J=7.32 Hz, 1H) 7.24-7.41 (m, 5H). LCMS:Anal. Calcd. for C₁₅H₂₂N₂O₃ 278.16 found 279.23 (M+H)⁺; HPLC PhenomenexLUNA C-18 4.6×50 mm, 0 to 100% B over 4 minutes, 1 minute hold time,A=90% water, 10% methanol, 0.1% TFA, B=10% water, 90% methanol, 0.1%TFA, RT=2.26 min, 97% homogeneity index.

Step 2;

(R)-2-(3,3-dimethylureido)-2-phenylacetic acid: To a stirred solution of((R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate (0.86 g, 3.10mmol) in CH₂Cl₂ (250 mL) was added TFA (15 mL) dropwise and theresulting solution was stirred at rt for 3 hours. The desired compoundwas then precipitated out of solution with a mixture of EtOAC:Hexanes(5:20), filtered off and dried under reduced pressure.(R)-2-(3,3-dimethylureido)-2-phenylacetic acid was isolated as a whitesolid (0.59 g, 86%) and used without further purification. ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.82 (s, 6H) 5.22 (d, J=7.32 Hz, 1H) 6.58 (d, J=7.32Hz, 1H) 7.28 (t, J=7.17 Hz, 1H) 7.33 (t, J=7.32 Hz, 2H) 7.38-7.43 (m,2H) 12.65 (s, 1H). LCMS: Anal. Calcd. for C₁₁H₁₄N₂O₃: 222.24. found:223.21 (M+H)⁺. HPLC XTERRA C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1minute hold time, A=90% water, 10% methanol, 0.2% H₃PO₄, B=10% water,90% methanol, 0.2% H₃PO₄, RT=0.75 min, 93% homogeneity index.

Cap-48

Step 1;

(R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate: To a stirredsolution of (R)-2-amino-2-phenylacetic acid hydrochloride (1.0 g, 4.10mmol) and

Hunig's base (1.0 mL, 6.15 mmol) in DMF (15 mL) was added cyclopentylisocyanate (0.46 mL, 4.10 mmol) dropwise and over 10 minutes. Afterstirring at room temperature for 3 hours, the reaction was concentratedunder reduced pressure and the resulting residue was traken up in ethylacetate. The organic layer was washed with H₂O and brine, dried (MgSO₄),filtered, and concentrated under reduced pressure. (R)-tert-butyl2-(3-cyclopentylureido)-2-phenylacetate was obtained as an opaque oil(1.32 g; 100%) and used without further purification. ¹H NMR (500 MHz,CD₃Cl-D) δ ppm 1.50-1.57 (m, 2H) 1.58-1.66 (m, 2H) 1.87-1.97 (m, 2H)3.89-3.98 (m, 1H) 5.37 (s, 1H) 7.26-7.38 (m, 5H). LCMS: Anal. Calcd. forC₁₈H₂₆N₂O₃ 318.19 found 319.21 (M+H)⁺; HPLC XTERRA C-18 3.0×50 mm, 0 to100% B over 4 minutes, 1 minute hold time, A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA, RT=2.82 min, 96%homogeneity index.

Step 2;

(R)-2-(3-cyclopentylureido)-2-phenylacetic acid: To a stirred solutionof (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate (1.31 g, 4.10mmol) in CH₂Cl₂ (25 mL) was added TFA (4 mL) and trietheylsilane (1.64mL; 10.3 mmol) dropwise, and the resulting solution was stirred at roomtemperature for 6 hours. The volatile components were removed underreduced pressure and the crude product was recrystallized in ethylacetate/pentanes to yield (R)-2-(3-cyclopentylureido)-2-phenylaceticacid as a white solid (0.69 g, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.17-1.35 (m, 2H) 1.42-1.52 (m, 2H) 1.53-1.64 (m, 2H) 1.67-1.80 (m, 2H)3.75-3.89 (m, 1H) 5.17 (d, J=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48(d, J=7.93 Hz, 1H) 7.24-7.40 (m, 5H) 12.73 (s, 1H). LCMS: Anal. Calcd.for C₁₄H₁₈N₂O₃: 262.31; found: 263.15 (M+H)⁺. HPLC XTERRA C-18 3.0×50mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10%methanol, 0.2% H₃PO₄, B=10% water, 90% methanol, 0.2% H₃PO₄, RT=1.24min, 100% homogeneity index.

Cap-49

To a stirred solution of 2-(benzylamino)acetic acid (2.0 g, 12.1 mmol)in formic acid (91 mL) was added formaldehyde (6.94 mL, 93.2 mmol).After five hours at 70° C., the reaction mixture was concentrated underreduced pressure to 20 mL and a white solid precipitated. Followingfiltration, the mother liquors were collected and further concentratedunder reduced pressure providing the crude product. Purification byreverse-phase preparative HPLC (Xterra 30×100 mm, detection at 220 nm,flow rate 35 mL/min, 0 to 35% B over 8 min; A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA) provided the titlecompound 2-(benzyl(methyl)-amino)acetic acid as its TFA salt (723 mg,33%) as a colorless wax. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.75 (s, 3H)4.04 (s, 2H) 4.34 (s, 2H) 7.29-7.68 (m, 5H). LCMS: Anal. Calcd. for:C₁₀H₁₃NO₂ 179.09. Found: 180.20 (M+H)⁺.

Cap-50

To a stirred solution of 3-methyl-2-(methylamino)butanoic acid (0.50 g,3.81 mmol) in water (30 mL) was added K₂CO₃ (2.63 g, 19.1 mmol) andbenzyl chloride (1.32 g, 11.4 mmol). The reaction mixture was stirred atambient temperature for 18 hours. The reaction mixture was extractedwith ethyl acetate (30 mL×2) and the aqueous layer was concentratedunder reduced pressure providing the crude product which was purified byreverse-phase preparative HPLC (Xterra 30×100 mm, detection at 220 nm,flow rate 40 mL/min, 20 to 80% B over 6 min; A=90% water, 10% methanol,0.1% TFA, B=10% water, 90% methanol, 0.1% TFA) to provide2-(benzyl(methyl)amino)-3-methylbutanoic acid, TFA salt (126 mg, 19%) asa colorless wax. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.98 (d, 3H) 1.07 (d,3H) 2.33-2.48 (m, 1H) 2.54-2.78 (m, 3H) 3.69 (s, 1H) 4.24 (s, 2H)7.29-7.65 (m, 5H). LCMS: Anal. Calcd. for: C₁₃H₁₉NO₂ 221.14. Found:222.28 (M+H)⁺.

Cap-51

Na₂CO₃ (1.83 g, 17.2 mmol) was added to NaOH (33 mL of 1M/H₂O, 33 mmol)solution of L-valine (3.9 g, 33.29 mmol) and the resulting solution wascooled with ice-water bath. Methyl chloroformate (2.8 mL, 36.1 mmol) wasadded dropwise over 15 min, the cooling bath was removed and thereaction mixture was stirred at ambient temperature for 3.25 hr. Thereaction mixture was washed with ether (50 mL, 3×), and the aqueousphase was cooled with ice-water bath and acidified with concentrated HClto a pH region of 1-2, and extracted with CH₂Cl₂ (50 mL, 3×). Theorganic phase was dried (MgSO₄) and evaporated in vacuo to afford Cap-51as a white solid (6 g). ¹H NMR for the dominant rotamer (DMSO-d₆, δ=2.5ppm, 500 MHz): 12.54 (s, 1H), 7.33 (d, J=8.6, 1H), 3.84 (dd, J=8.4, 6.0,1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.87 (m, 6H). HRMS: Anal. Calcd. for[M+H]⁺ C₇H₁₄NO₄: 176.0923. found 176.0922.

Cap 51 (Alternate Route)

DIEA (137.5 mL, 0.766 mol) was added to a suspension of (S)-tert-butyl2-amino-3-methylbutanoate hydrochloride (75.0 g, 0.357 mol) in THF (900mL), and the mixture was cooled to 0° C. (ice/water bath). Methylchloroformate (29.0 mL, 0.375 mol) was added dropwise over 45 min, thecooling bath was removed and the heterogeneous mixture was stirred atambient temperature for 3 h. The solvent was removed under diminishedpressure and the residue partitioned between EtOAc and water (1 L each).The organic layer was washed with H₂O (1 L) and brine (1 L), dried(MgSO₄), filtered and concentrated under diminished pressure. The crudematerial was passed through a plug of silica gel (1 kg), eluting withhexanes (4 L) and 15:85 EtOAc/hexanes (4 L) to afford (S)-tert-butyl2-(methoxycarbonylamino)-3-methylbutanoate as a clear oil (82.0 g, 99%yield). ¹H-NMR (500 MHz, DMSO-d₆, δ=2.5 ppm) 7.34 (d, J=8.6, 1H), 3.77(dd, J=8.6, 6.1, 1H), 3.53 (s, 3H), 1.94-2.05 (m, 1H), 1.39 (s, 9H),0.83-0.92 (m, 6H). ¹³C-NMR (126 MHz, DMSO-d₆, δ=39.2 ppm) 170.92,156.84, 80.38, 60.00, 51.34, 29.76, 27.62, 18.92, 17.95. LC/MS: [M+Na]⁺254.17.

Trifluoroacetic acid (343 mL, 4.62 mol) and Et₃SiH (142 mL, 0.887 mol)were added sequentially to a solution of (S)-tert-butyl2-(methoxycarbonylamino)-3-methylbutanoate (82.0 g, 0.355 mol) in CH₂Cl₂(675 mL), and the mixture was stirred at ambient temperature for 4 h.The volatile component was removed under diminished pressure and theresultant oil triturated with petroleum ether (600 mL) to afford a whitesolid, which was filtered and washed with hexanes (500 mL) and petroleumether (500 mL). Recrystallization from EtOAc/petroleum ether affordedCap-51 as white flaky crystals (54.8 g, 88% yield). MP=108.5-109.5° C.¹H NMR (500 MHz, DMSO-d₆, δ=2.5 ppm) 12.52 (s, 1H), 7.31 (d, J=8.6, 1H),3.83 (dd, J=8.6, 6.1, 1H), 3.53 (s, 3H), 1.94-2.07 (m, 1H), 0.86 (dd,J=8.9, 7.0, 6 H). ¹³C NMR (126 MHz, DMSO-d₆, δ=39.2 ppm) 173.30, 156.94,59.48, 51.37, 29.52, 19.15, 17.98. LC/MS: [M+H]⁺=176.11. Anal. Calcd.for C₇H₁₃NO₄: C, 47.99; H, 7.48; N, 7.99. Found: C, 48.17; H, 7.55; N,7.99. Optical Rotation: [α]_(D)=−4.16 (12.02 mg/mL; MeOH). Opticalpurity: >99.5% ee. Note: the optical purity assessment was made on themethyl ester derivative of Cap-51, which was prepared under a standardTMSCHN₂ (benzene/MeOH) esterification protocol. HPLC analyticalconditions: column, ChiralPak AD-H (4.6×250 mm, 5 μm); solvent, 95%heptane/5% IPA (isocratic); flow rate, 1 mL/min; temperature, 35° C.; UVmonitored at 205 nm.

[Note: Cap 51 could also be purchased from Flamm.]

Cap-52 (Same as Cap-12)

Cap-52 was synthesized from L-alanine according to the proceduredescribed for the synthesis of Cap-51. For characterization purposes, aportion of the crude material was purified by a reverse phase HPLC(H₂O/methanol/TFA) to afford Cap-52 as a colorless viscous oil. ¹H NMR(DMSO-d₆, δ=2.5 ppm, 500 MHz): 12.49 (br s, 1H), 7.43 (d, J=7.3, 0.88H),7.09 (app br s, 0.12H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, J=7.3, 3H).

Cap-53 to -64 were prepared from appropriate starting materialsaccording to the procedure described for the synthesis of Cap-51, withnoted modifications if any.

Cap Structure Data Cap-53a: (R) Cap-53b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.51 (br s, 1H), 7.4 (d, J =7.9, 0.9H), 7.06 (app s, 0.1H), 3.86-3.82 (m, 1H), 3.53 (s, 3H),1.75-1.67 (m, 1H), 1.62- 1.54 (m, 1H), 0.88 (d, J = 7.3, 3H). RT = 0.77minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + Na]⁺ C₆H₁₁NNaO₄: 184.06;found 184.07. HRMS Calcd. for [M + Na]⁺ C₆H₁₁NNaO₄: 184.0586; found184.0592. Cap-54a: (R) Cap-54b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.48 (s, 1H), 7.58 (d, J =7.6, 0.9H), 7.25 (app s, 0.1H), 3.52 (s, 3H), 3.36-3.33 (m, 1H),1.10-1.01 (m, 1H), 0.54-0.49 (m, 1H), 0.46-0.40 (m, 1H), 0.39-0.35 (m,1H), 0.31-0.21 (m, 1H). HRMS Calcd. for [M + H]⁺ C₇H₁₂NO₄: 174.0766;found 174.0771 Cap-55

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.62 (s, 1H), 7.42 (d, J =8.2, 0.9H), 7.07 (app s, 0.1H), 5.80-5.72 (m, 1H), 5.10 (d, J = 17.1,1H), 5.04 (d, J = 10.4, 1H), 4.01-3.96 (m, 1H), 3.53 (s, 3H), 2.47-2.42(m, 1H), 2.35-2.29 (m, 1H). Cap-56

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.75 (s, 1H), 7.38 (d, J =8.3, 0.9H), 6.96 (app s, 0.1H), 4.20-4.16 (m, 1H), 3.60-3.55 (m, 2H),3.54 (s, 3H), 3.24 (s, 3H). Cap-57

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.50 (s, 1H), 8.02 (d, J =7.7, 0.08H), 7.40 (d, J = 7.9, 0.76H), 7.19 (d, J = 8.2, 0.07H), 7.07(d, J = 6.7, 0.09H), 4.21-4.12 (m, 0.08H), 4.06-3.97 (m, 0.07H),3.96-3.80 (m, 0.85H), 3.53 (s, 3H), 1.69-1.51 (m, 2H), 1.39-1.26 (m,2H), 0.85 (t, J = 7.4, 3H). LC (Cond. 2): RT = 1.39 LC/MS: Anal. Calcd.for [M + H]⁺ C₇H₁₄NO₄: 176.09; found 176.06. Cap-58

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.63 (br s, 1H), 7.35 (s,1H), 7.31 (d, J = 8.2, 1H), 6.92 (s, 1H), 4.33-4.29 (m, 1H), 3.54 (s,3H), 2.54 (dd, J = 15.5, 5.4, 1H), 2.43 (dd, J = 15.6, 8.0, 1H). RT =0.16 min (Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₆H₁₁N₂O₅: 191.07;found 191.14. Cap-59a: (R) Cap-59b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.49 (br s, 1H), 7.40 (d, J =7.3, 0.89H), 7.04 (br s, 0.11H), 4.00-3.95 (m, 3H), 1.24 (d, J = 7.3,3H), 1.15 (t, J = 7.2, 3H). HRMS: Anal. Calcd. for [M + H]⁺ C₆H₁₂NO₄:162.0766; found 162.0771. Cap-60

The crude material was purified with a reverse phase HPLC (H₂O/MeOH/TFA)to afford a colorless viscous oil that crystallized to a white solidupon exposure to high vacuum. ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ12.38 (br s, 1H), 7.74 (s, 0.82H), 7.48 (s, 0.18H), 3.54/3.51 (two s,3H), 1.30 (m, 2H), 0.98 (m, 2H). HRMS: Anal. Calcd. for [M + H]⁺C₆H₁₀NO₄: 160.0610; found 160.0604. Cap-61

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.27 (br s, 1H), 7.40 (br s,1H), 3.50 (s, 3H), 1.32 (s, 6H). HRMS: Anal. Calcd. for [M + H]⁺C₆H₁₂NO₄: 162.0766; found 162.0765. Cap-62

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.74 (br s, 1H), 4.21 (d, J =10.3, 0.6H), 4.05 (d, J = 10.0, 0.4H), 3.62/3.60 (two singlets, 3H), 3.0(s, 3H), 2.14-2.05 (m, 1H), 0.95 (d, J = 6.3, 3H), 0.81 (d, J = 6.6,3H). LC/MS: Anal. Calcd. for [M − H]⁻ C₈H₁₄NO₄: 188.09; found 188.05.Cap-63

[Note: the reaction was allowed to run for longer than what was notedfor the general procedure.] ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz):12.21 (br s, 1H), 7.42 (br s, 1H), 3.50 (s, 3H), 2.02-1.85 (m, 4H),1.66-1.58 (m, 4H). LC/MS: Anal. Calcd. for [M + H]⁺ C₈H₁₄NO₄: 188.09;found 188.19. Cap-64

[Note: the reaction was allowed to run for longer than what was notedfor the general procedure.] ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz):12.35 (br s, 1H), 7.77 (s, 0.82H), 7.56/7.52 (overlapping br s, 0.18H),3.50 (s, 3H), 2.47-2.40 (m, 2H), 2.14-2.07 (m, 2H), 1.93-1.82 (m, 2H).

Cap-65

Methyl chloroformate (0.65 mL, 8.39 mmol) was added dropwise over 5 minto a cooled (ice-water) mixture of Na₂CO₃ (0.449 g, 4.23 mmol), NaOH(8.2 mL of 1M/H₂O, 8.2 mmol) and (S)-2-amino-3-hydroxy-3-methylbutanoicacid (1.04 g, 7.81 mmol). The reaction mixture was stirred for 45 min,and then the cooling bath was removed and stirring was continued for anadditional 3.75 hr. The reaction mixture was washed with CH₂Cl₂, and theaqueous phase was cooled with ice-water bath and acidified withconcentrated HCl to a pH region of 1-2. The volatile component wasremoved in vacuo and the residue was taken up in a 2:1 mixture ofMeOH/CH₂Cl₂ (15 mL) and filtered, and the filterate was rotervaped toafford Cap-65 as a white semi-viscous foam (1.236 g). ¹H NMR (DMSO-d₆,δ=2.5 ppm, 400 MHz): δ 6.94 (d, J=8.5, 0.9; H), 6.53 (br s, 0.1H), 3.89(d, J=8.8, 1H), 2.94 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H).

Cap-66 and -67 were prepared from appropriate commercially availablestarting materials by employing the procedure described for thesynthesis of Cap-65.

Cap-66

¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 12.58 (br s, 1H), 7.07 (d,J=8.3, 0.13H), 6.81 (d, J=8.8, 0.67H), 4.10-4.02 (m, 1.15H), 3.91 (dd,J=9.1, 3.5, 0.85H), 3.56 (s, 3H), 1.09 (d, J=6.2, 3H). [Note: only thedominant signals of NH were noted].

Cap-67

¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 12.51 (br s, 1H), 7.25 (d, J=8.4,0.75H), 7.12 (br d, J=0.4, 0.05H), 6.86 (br s, 0.08H), 3.95-3.85 (m,2H), 3.54 (s, 3H), 1.08 (d, J=6.3, 3H). [Note: only the dominant signalsof NH were noted].

Cap-68

Methyl chloroformate (0.38 ml, 4.9 mmol) was added drop-wise to amixture of 1N NaOH (aq) (9.0 ml, 9.0 mmol), 1M NaHCO₃ (aq) (9.0 ml, 9.0mol), L-aspartic acid β-benzyl ester (1.0 g, 4.5 mmol) and Dioxane (9ml). The reaction mixture was stirred at ambient conditions for 3 hr,and then washed with Ethyl acetate (50 ml, 3×). The aqueous layer wasacidified with 12N HCl to a pH˜1-2, and extracted with ethyl acetate(3×50 ml). The combined organic layers were washed with brine, dried(Na₂SO₄), filtered, and concentrated in vacuo to afford Cap-68 as alight yellow oil (1.37 g; mass is above theoretical yield, and theproduct was used without further purification). ¹H NMR (DMSO-d₆, δ=2.5ppm, 500 MHz): δ 12.88 (br s, 1H), 7.55 (d, J=8.5, 1H), 7.40-7.32 (m,5H), 5.13 (d, J=12.8, 1H), 5.10 (d, J=12.9, 1H), 4.42-4.38 (m, 1H), 3.55(s, 3H), 2.87 (dd, J=16.2, 5.5, 1H), 2.71 (dd, J=16.2, 8.3, 1H). LC(Cond. 2): RT=1.90 min; LC/MS: Anal. Calcd. For [M+H]⁺ C₁₃H₁₆NO₆:282.10. found 282.12.

Cap-69a and -69b

NaCNBH₃ (2.416 g, 36.5 mmol) was added in batches to a chilled (˜15° C.)water (17 mL)/MeOH (10 mL) solution of alanine (1.338 g, 15.0 mmol). Afew minutes later acetaldehyde (4.0 mL, 71.3 mmol) was added drop-wiseover 4 min, the cooling bath was removed, and the reaction mixture wasstirred at ambient condition for 6 hr. An additional acetaldehyde (4.0mL) was added and the reaction was stirred for 2 hr. Concentrated HClwas added slowly to the reaction mixture until the pH reached ˜1.5, andthe resulting mixture was heated for 1 hr at 40° C. Most of the volatilecomponent was removed in vacuo and the residue was purified with aDowex® 50WX8-100 ion-exchange resin (column was washed with water, andthe compound was eluted with dilute NH₄OH, prepared by mixing 18 ml ofNH₄OH and 282 ml of water) to afford Cap-69 (2.0 g) as an off-white softhygroscopic solid. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 3.44 (q,J=7.1, 1H), 2.99-2.90 (m, 2H), 2.89-2.80 (m, 2H), 1.23 (d, J=7.1, 3H),1.13 (t, J=7.3, 6H).

Cap-70 to −74× were prepared according to the procedure described forthe synthesis of Cap-69 by employing appropriate starting materials.

Cap-70a: (R) Cap-70b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 3.42 (q, J = 7.1, 1H),2.68-2.60 (m, 4H), 1.53-1.44 (m, 4H), 1.19 (d, J = 7.3, 3H), 0.85 (t, J= 7.5, 6H). LC/MS: Anal. Calcd. for [M + H]⁺ C₉H₂₀NO₂: 174.15; found174.13. Cap-71a: (R) Cap-71b: (S)

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 3.18-3.14 (m, 1H), 2.84-2.77(m, 2H), 2.76-2.68 (m, 2H), 1.69-1.54 (m, 2H), 1.05 (t, J = 7.2, 6H),0.91 (t, J = 7.3, 3H). LC/MS: Anal. Calcd. for [M + H]⁺ C₈H₁₈NO₂:160.13; found 160.06. Cap-72

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 2.77-2.66 (m, 3H), 2.39-2.31(m, 2H), 1.94-1.85 (m, 1H), 0.98 (t, J = 7.1, 6H), 0.91 (d, J = 6.5,3H), 0.85 (d, J = 6.5, 3H). LC/MS: Anal. Calcd. for [M + H]⁺ C₉H₂₀NO₂:174.15; found 174.15. Cap-73

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 9.5 (br s, 1H), 3.77 (dd, J =10.8, 4.1, 1H), 3.69-3.61 (m, 2H), 3.26 (s, 3H), 2.99-2.88 (m, 4H), 1.13(t, J = 7.2, 6H). Cap-74

¹H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 7.54 (s, 1H), 6.89 (s, 1H),3.81 (t, J = 6.6, k, 1H), 2.82-2.71 (m, 4H), 2.63 (dd, J = 15.6, 7.0,1H), 2.36 (dd, J = 15.4, 6.3, 1H), 1.09 (t, J = 7.2, 6H). RT = 0.125minutes (Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₈H₁₇N₂O₃: 189.12;found 189.13. Cap-74x

LC/MS: Anal. Calcd. for [M + H]⁺ C₁₀H₂₂NO₂: 188.17; found 188.21

Cap-75

Cap-75, Step A

NaBH₃CN (1.6 g, 25.5 mmol) was added to a cooled (ice/water bath) water(25 ml)/methanol (15 ml) solution of H-D-Ser-OBzl HCl (2.0 g, 8.6 mmol).Acetaldehyde (1.5 ml, 12.5 mmol) was added drop-wise over 5 min, thecooling bath was removed, and the reaction mixture was stirred atambient condition for 2 hr. The reaction was carefully quenched with 12NHCl and concentrated in vacuo. The residue was dissolved in water andpurified with a reverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA saltof (R)-benzyl 2-(diethylamino)-3-hydroxypropanoate as a colorlessviscous oil (1.9 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): δ 9.73 (br s,1H), 7.52-7.36 (m, 5H), 5.32 (d, J=12.2, 1H), 5.27 (d, J=12.5, 1H),4.54-4.32 (m, 1H), 4.05-3.97 (m, 2H), 3.43-3.21 (m, 4H), 1.23 (t, J=7.2,6H). LC/MS (Cond. 2): RT=1.38 min; LC/MS: Anal. Calcd. for [M+H]⁺C₁₄H₂₂NO₃: 252.16. found 252.19.

Cap-75

NaH (0.0727 g, 1.82 mmol, 60%) was added to a cooled (ice-water) THF(3.0 mL) solution of the TFA salt (R)-benzyl2-(diethylamino)-3-hydroxypropanoate (0.3019 g, 0.8264 mmol) preparedabove, and the mixture was stirred for 15 min. Methyl iodide (56 μL,0.90 mmol) was added and stirring was continued for 18 hr while allowingthe bath to thaw to ambient condition. The reaction was quenched withwater and loaded onto a MeOH pre-conditioned MCX (6 g) cartridge, andwashed with methanol followed by compound elution with 2N NH₃/Methanol.Removal of the volatile component in vacuo afforded Cap-75, contaminatedwith (R)-2-(diethylamino)-3-hydroxypropanoic acid, as a yellowsemi-solid (100 mg). The product was used as is without furtherpurification.

Cap-76

NaCNBH₃ (1.60 g, 24.2 mmol) was added in batches to a chilled (˜15° C.)water/MeOH (12 mL each) solution of(S)-4-amino-2-(tert-butoxycarbonylamino) butanoic acid (2.17 g, 9.94mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was addeddrop-wise over 2 min, the cooling bath was removed, and the reactionmixture was stirred at ambient condition for 3.5 hr. An additionalacetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirredfor 20.5 hr. Most of the MeOH component was removed in vacuo, and theremaining mixture was treated with concentrated HCl until its pH reached˜1.0 and then heated for 2 hr at 40° C. The volatile component wasremoved in vacuo, and the residue was treated with 4 M HCl/dioxane (20mL) and stirred at ambient condition for 7.5 hr. The volatile componentwas removed in vacuo and the residue was purified with Dowex® 50WX8-100ion-exchange resin (column was washed with water and the compound waseluted with dilute NH₄OH, prepared from 18 ml of NH₄OH and 282 ml ofwater) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acidas an off-white solid (1.73 g).

Methyl chloroformate (0.36 mL, 4.65 mmol) was added drop-wise over 11min to a cooled (ice-water) mixture of Na₂CO₃ (0.243 g, 2.29 mmol), NaOH(4.6 mL of 1M/H₂O, 4.6 mmol) and the above product (802.4 mg). Thereaction mixture was stirred for 55 min, and then the cooling bath wasremoved and stirring was continued for an additional 5.25 hr. Thereaction mixture was diluted with equal volume of water and washed withCH₂Cl₂ (30 mL, 2×), and the aqueous phase was cooled with ice-water bathand acidified with concentrated HCl to a pH region of 2. The volatilecomponent was then removed in vacuo and the crude material wasfree-based with MCX resin (6.0 g; column was washed with water, andsample was eluted with 2.0 M NH₃/MeOH) to afford impure Cap-76 as anoff-white solid (704 mg). ¹H NMR (MeOH-d₄, δ=3.29 ppm, 400 MHz): δ 3.99(dd, J=7.5, 4.7, 1H), 3.62 (s, 3H), 3.25-3.06 (m, 6H), 2.18-2.09 (m,1H), 2.04-1.96 (m, 1H), 1.28 (t, J=7.3, 6H). LC/MS: Anal. Calcd. for[M+H]⁺ C₁₀H₂₁N₂O₄: 233.15. found 233.24.

Cap-77a and -77b

The synthesis of Cap-77 was conducted according to the proceduredescribed for Cap-7 by using 7-azabicyclo[2.2.1]heptane for the SN₂displacement step, and by effecting the enantiomeric separation of theintermediate benzyl 2-(7-azabicyclo[2.2.1]heptan-7-yl)-2-phenylacetateusing the following condition: the intermediate (303.7 mg) was dissolvedin ethanol, and the resulting solution was injected on a chiral HPLCcolumn (Chiracel AD-H column, 30×250 mm, 5 um) eluting with 90% CO₂-10%EtOH at 70 mL/min, and a temperature of 35° C. to provide 124.5 mg ofenantiomer-1 and 133.8 mg of enantiomer-2. These benzyl esters werehydrogenolysed according to the preparation of Cap-7 to provide Cap-77:¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.55 (m, 2H), 7.38-7.30 (m, 3H),4.16 (s, 1H), 3.54 (app br s, 2H), 2.08-1.88 (m, 4H), 1.57-1.46 (m, 4H).LC (Cond. 1): RT=0.67 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₄H₁₈NO₂:232.13. found 232.18. HRMS: Anal. Calcd. for [M+H]⁺ C₁₄H₁₈NO₂: 232.1338.found 232.1340.

Cap-78

NaCNBH₃ (0.5828 g, 9.27 mmol) was added to a mixture of the HCl salt of(R)-2-(ethylamino)-2-phenylacetic acid (an intermediate in the synthesisof Cap-3; 0.9923 mg, 4.60 mmol) and(1-ethoxycyclopropoxy)trimethylsilane (1.640 g, 9.40 mmol) in MeOH (10mL), and the semi-heterogeneous mixture was heated at 50° C. with an oilbath for 20 hr. More (1-ethoxycyclopropoxy)trimethylsilane (150 mg, 0.86mmol) and NaCNBH₃ (52 mg, 0.827 mmol) were added and the reactionmixture was heated for an additional 3.5 hr. It was then allowed to coolto ambient temperature and acidified to a ˜pH region of 2 withconcentrated HCl, and the mixture was filtered and the filtrate wasrotervaped. The resulting crude material was taken up in i-PrOH (6 mL)and heated to effect dissolution, and the non-dissolved part wasfiltered off and the filtrate concentrated in vacuo. About ⅓ of theresultant crude material was purified with a reverse phase HPLC(H₂O/MeOH/TFA) to afford the TFA salt of Cap-78 as a colorless viscousoil (353 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz; after D₂O exchange):δ 7.56-7.49 (m, 5H), 5.35 (S, 1H), 3.35 (m, 1H), 3.06 (app br s, 1H),2.66 (m, 1H), 1.26 (t, J=7.3, 3H), 0.92 (m, 1H), 0.83-0.44 (m, 3H). LC(Cond. 1): RT=0.64 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₈NO₂:220.13. found 220.21. HRMS: Anal. Calcd. for [M+H]⁺ C₁₃H₁₈NO₂: 220.1338.found 220.1343.

Cap-79

Ozone was bubbled through a cooled (−78° C.) CH₂Cl₂ (5.0 mL) solutionCap-55 (369 mg, 2.13 mmol) for about 50 min until the reaction mixtureattained a tint of blue color. Me₂S (10 pipet drops) was added, and thereaction mixture was stirred for 35 min. The −78° C. bath was replacedwith a −10° C. bath and stirring continued for an additional 30 min, andthen the volatile component was removed in vacuo to afford a colorlessviscous oil.

NaBH₃CN (149 mg, 2.25 mmol) was added to a MeOH (5.0 mL) solution of theabove crude material and morpholine (500 μL, 5.72 mmol) and the mixturewas stirred at ambient condition for 4 hr. It was cooled to ice-watertemperature and treated with concentrated HCl to bring its pH to ˜2.0,and then stirred for 2.5 hr. The volatile component was removed invacuo, and the residue was purified with a combination of MCX resin(MeOH wash; 2.0 N NH₃/MeOH elution) and a reverse phase HPLC(H₂O/MeOH/TFA) to afford Cap-79 containing unknown amount of morpholine.

In order to consume the morpholine contaminant, the above material wasdissolved in CH₂Cl₂ (1.5 mL) and treated with Et₃N (0.27 mL, 1.94 mmol)followed by acetic anhydride (0.10 mL, 1.06 mmol) and stirred at ambientcondition for 18 hr. THF (1.0 mL) and H₂O (0.5 mL) were added andstirring continued for 1.5 hr. The volatile component was removed invacuo, and the resultant residue was passed through MCX resin (MeOHwash; 2.0 N NH₃/MeOH elution) to afford impure Cap-79 as a brown viscousoil, which was used for the next step without further purification.

Cap-80a and -80b

SOCl₂ (6.60 mL, 90.5 mmol) was added drop-wise over 15 min to a cooled(ice-water) mixture of (S)-3-amino-4-(benzyloxy)-4-oxobutanoic acid(10.04 g, 44.98 mmol) and MeOH (300 mL), the cooling bath was removedand the reaction mixture was stirred at ambient condition for 29 hr.Most of the volatile component was removed in vacuo and the residue wascarefully partitioned between EtOAc (150 mL) and saturated NaHCO₃solution. The aqueous phase was extracted with EtOAc (150 mL, 2×), andthe combined organic phase was dried (MgSO₄), filtered, and concentratedin vacuo to afford (S)-1-benzyl 4-methyl 2-aminosuccinate as a colorlessoil (9.706 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.40-7.32 (m,5H), 5.11 (s, 2H), 3.72 (app t, J=6.6, 1H), 3.55 (s, 3H), 2.68 (dd,J=15.9, 6.3, 1H), 2.58 (dd, J=15.9, 6.8, 1H), 1.96 (s, 2H). LC (Cond.1): RT=0.90 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₆NO₄: 238.11. found238.22.

Pb(NO₃)₂ (6.06 g, 18.3 mmol) was added over 1 min to a CH₂Cl₂ (80 mL)solution of (S)-1-benzyl 4-methyl 2-aminosuccinate (4.50 g, 19.0 mmol),9-bromo-9-phenyl-9H-fluorene (6.44 g, 20.0 mmol) and Et₃N (3.0 mL, 21.5mmol), and the heterogeneous mixture was stirred at ambient conditionfor 48 hr. The mixture was filtered and the filtrate was treated withMgSO₄ and filtered again, and the final filtrate was concentrated. Theresulting crude material was submitted to a Biotage purification (350 gsilica gel, CH₂Cl₂ elution) to afford (S)-1-benzyl 4-methyl2-(9-phenyl-9H-fluoren-9-ylamino)succinate as highly viscous colorlessoil (7.93 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 7.82 (m, 2H),7.39-7.13 (m, 16H), 4.71 (d, J=12.4, 1H), 4.51 (d, J=12.6, 1H), 3.78 (d,J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H, partiallyoverlapped with solvent). LC (Cond. 1): RT=2.16 min; LC/MS: Anal. Calcd.for [M+H]⁺ C₃₁H₂₈NO₄: 478.20. found 478.19.

LiHMDS (9.2 mL of 1.0 M/THF, 9.2 mmol) was added drop-wise over 10 minto a cooled (−78° C.) THF (50 mL) solution of (S)-1-benzyl 4-methyl2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.907 g, 8.18 mmol) andstirred for ˜1 hr. MeI (0.57 mL, 9.2 mmol) was added drop-wise over 8min to the mixture, and stirring was continued for 16.5 hr whileallowing the cooling bath to thaw to room temperature. After quenchingwith saturated NH₄Cl solution (5 mL), most of the organic component wasremoved in vacuo and the residue was partitioned between CH₂Cl₂ (100 mL)and water (40 mL). The organic layer was dried (MgSO₄), filtered, andconcentrated in vacuo, and the resulting crude material was purifiedwith a Biotage (350 g silica gel; 25% EtOAc/hexanes) to afford 3.65 g ofa 2S/3S and 2S/3R diastereomeric mixtures of 1-benzyl 4-methyl3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate in ˜1.0:0.65 ratio(¹H NMR). The stereochemistry of the dominant isomer was not determinedat this juncture, and the mixture was submitted to the next step withoutseparation. Partial ¹H NMR data (DMSO-d₆, δ=2.5 ppm, 400 MHz): majordiastereomer, δ 4.39 (d, J=12.3, 1H of CH₂), 3.33 (s, 3H, overlappedwith H₂O signal), 3.50 (d, J=10.9, NH), 1.13 (d, J=7.1, 3H); minordiastereomer, δ 4.27 (d, J=12.3, 1H of CH₂), 3.76 (d, J=10.9, NH), 3.64(s, 3H), 0.77 (d, J=7.0, 3H). LC (Cond. 1): RT=2.19 min; LC/MS: Anal.Calcd. for [M+H]⁺ C₃₂H₃₀NO₄: 492.22. found 492.15.

Diisobutylaluminum hydride (20.57 ml of 1.0 M in hexanes, 20.57 mmol)was added drop-wise over 10 min to a cooled (−78° C.) THF (120 mL)solution of (2S)-1-benzyl 4-methyl3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.37 g, 6.86 mmol)prepared above, and stirred at −78° C. for 20 hr. The reaction mixturewas removed from the cooling bath and rapidly poured into ˜1M H₃PO₄/H₂O(250 mL) with stirring, and the mixture was extracted with ether (100mL, 2×). The combined organic phase was washed with brine, dried(MgSO₄), filtered and concentrated in vacuo. A silica gel mesh of thecrude material was prepared and submitted to chromatography (25%EtOAc/hexanes; gravity elution) to afford 1.1 g of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate,contaminated with benzyl alcohol, as a colorless viscous oil and(2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate containingthe (2S,3R) stereoisomer as an impurity. The later sample wasresubmitted to the same column chromatography purification conditions toafford 750 mg of purified material as a white foam. [Note: the (2S,3S)isomer elutes before the (2S,3R) isomer under the above condition].(2S,3S) isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): 7.81 (m, 2H),7.39-7.08 (m, 16H), 4.67 (d, J=12.3, 1H), 4.43 (d, J=12.4, 1H), 4.21(app t, J=5.2, OH), 3.22 (d, J=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H),˜2.5 (m, 1H, overlapped with the solvent signal), 1.58 (m, 1H), 0.88 (d,J=6.8, 3H). LC (Cond. 1): RT=2.00 min; LC/MS: Anal. Calcd. for [M+H]⁺C₃₁H₃₀NO₃: 464.45; found 464.22. (2S,3R) isomer: ¹H NMR (DMSO-d₆, δ=2.5ppm, 400 MHz): 7.81 (d, J=7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, J=12.1,1H), 4.50 (app t, J=4.9, 1H), 4.32 (d, J=12.1, 1H), 3.59-3.53 (m, 2H),3.23 (m, 1H), 2.44 (dd, J=9.0, 8.3, 1H), 1.70 (m, 1H), 0.57 (d, J=6.8,3H). LC (Cond. 1): RT=1.92 min; LC/MS: Anal. Calcd. for [M+H]⁺C₃₁H₃₀NO₃: 464.45. found 464.52.

The relative stereochemical assignments of the DIBAL-reduction productswere made based on NOE studies conducted on lactone derivatives preparedfrom each isomer by employing the following protocol: LiHMDS (50 μL of1.0 M/THF, 0.05 mmol) was added to a cooled (ice-water) THF (2.0 mL)solution of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (62.7 mg,0.135 mmol), and the reaction mixture was stirred at similar temperaturefor ˜2 hr. The volatile component was removed in vacuo and the residuewas partitioned between CH₂Cl₂ (30 mL), water (20 mL) and saturatedaqueous NH₄Cl solution (1 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo, and the resulting crude materialwas submitted to a Biotage purification (40 g silica gel; 10-15%EtOAc/hexanes) to afford(3S,4S)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-oneas a colorless film of solid (28.1 mg). (2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate waselaborated similarly to(3S,4R)-4-methyl-3-(9-phenyl-9H-fluoren-9-ylamino)dihydrofuran-2(3H)-one.(3S,4S)-lactone isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz), 7.83 (d,J=7.5, 2H), 7.46-7.17 (m, 11H), 4.14 (app t, J=8.3, 1H), 3.60 (d, J=5.8,NH), 3.45 (app t, J=9.2, 1H), ˜2.47 (m, 1H, partially overlapped withsolvent signal), 2.16 (m, 1H), 0.27 (d, J=6.6, 3H). LC (Cond. 1):RT=1.98 min; LC/MS: Anal. Calcd. for [M+Na]⁺ C₂₄H₂₁NNaO₂: 378.15. found378.42. (3S,4R)-lactone isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz),7.89 (d, J=7.6, 1H), 7.85 (d, J=7.3, 1H), 7.46-7.20 (m, 11H), 3.95 (dd,J=9.1, 4.8, 1H), 3.76 (d, J=8.8, 1H), 2.96 (d, J=3.0, NH), 2.92 (dd,J=6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, J=7.0, 3H). LC (Cond. 1): RT=2.03min; LC/MS: Anal. Calcd. for [M+Na]⁺ C₂₄H₂₁NNaO₂: 378.15. found 378.49.

TBDMS-Cl (48 mg, 0.312 mmol) followed by imidazole (28.8 mg, 0.423 mmol)were added to a CH₂Cl₂ (3 ml) solution of (2S,3S)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (119.5 mg,0.258 mmol), and the mixture was stirred at ambient condition for 14.25hr. The reaction mixture was then diluted with CH₂Cl₂ (30 mL) and washedwith water (15 mL), and the organic layer was dried (MgSO₄), filtered,and concentrated in vacuo. The resultant crude material was purifiedwith a Biotage (40 g silica gel; 5% EtOAc/hexanes) to afford(2S,3S)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate,contaminated with TBDMS based impurities, as a colorless viscous oil(124.4 mg). (2S,3R)-benzyl4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate waselaborated similarly to (2S,3R)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate.(2S,3S)-silyl ether isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz), 7.82(d, J=4.1, 1H), 7.80 (d, J=4.0, 1H), 7.38-7.07 (m, 16H), 4.70 (d,J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.28-3.19 (m, 3H), 2.56 (dd, J=10.1,5.5, 1H), 1.61 (m, 1H), 0.90 (d, J=6.8, 3H), 0.70 (s, 9H), −0.13 (s,3H), −0.16 (s, 3H). LC (Cond. 1, where the run time was extended to 4min): RT=3.26 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₃₇H₄₄NO₃Si: 578.31.found 578.40. (2S,3R)-silyl ether isomer: ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz), 7.82 (d, J=3.0, 1H), 7.80 (d, J=3.1, 1H), 7.39-7.10 (m, 16H),4.66 (d, J=12.4, 1H), 4.39 (d, J=12.4, 1H), 3.61 (dd, J=9.9, 5.6, 1H),3.45 (d, J=9.5, 1H), 3.41 (dd, J=10, 6.2, 1H), 2.55 (dd, J=9.5, 7.3,1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d, J=7.1, 3H), −0.06 (s, 3H),−0.08 (s, 3H).

A balloon of hydrogen was attached to a mixture of (2S,3S)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate(836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) and themixture was stirred at room temperature for ˜21 hr, where the balloonwas recharged with H₂ as necessary. The reaction mixture was dilutedwith CH₂Cl₂ and filtered through a pad of diatomaceous earth(Celite-545®), and the pad was washed with EtOAc (200 mL), EtOAc/MeOH(1:1 mixture, 200 mL) and MeOH (750 mL). The combined organic phase wasconcentrated, and a silica gel mesh was prepared from the resultingcrude material and submitted to a flash chromatography (8:2:1 mixture ofEtOAc/1-PrOH/H₂O) to afford(2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid asa white fluffy solid (325 mg). (2S,3R)-benzyl4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoatewas similarly elaborated to(2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid.(2S,3S)-amino acid isomer: ¹H NMR (Methanol-d₄, δ=3.29 ppm, 400 MHz),3.76 (dd, J=10.5, 5.2, 1H), 3.73 (d, J=3.0, 1H), 3.67 (dd, J=10.5, 7.0,1H), 2.37 (m, 1H), 0.97 (d, J=7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H).LC/MS: Anal. Calcd. for [M+H]⁺ C₁₁H₂₆NO₃Si: 248.17. found 248.44.(2S,3R)-amino acid isomer: ¹H NMR (Methanol-d₄, δ=3.29 ppm, 400 MHz),3.76-3.75 (m, 2H), 3.60 (d, J=4.1, 1H), 2.16 (m, 1H), 1.06 (d, J=7.3,3H), 0.91 (s, 9H), 0.09 (s, 6H). Anal. Calcd. for [M+H]⁺ C₁₁H₂₆NO₃Si:248.17. found 248.44.

Water (1 mL) and NaOH (0.18 mL of 1.0 M/H₂O, 0.18 mmol) were added to amixture of(2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid(41.9 mg, 0.169 mmol) and Na₂CO₃ (11.9 mg, 0.112 mmol), and sonicatedfor about 1 min to effect dissolution of reactants. The mixture was thencooled with an ice-water bath, methyl chloroformate (0.02 mL, 0.259mmol) was added over 30 s, and vigorous stirring was continued atsimilar temperature for 40 min and then at ambient temperature for 2.7hr. The reaction mixture was diluted with water (5 mL), cooled withice-water bath and treated drop-wise with 1.0 N HCl aqueous solution(˜0.23 mL). The mixture was further diluted with water (10 mL) andextracted with CH₂Cl₂ (15 mL, 2×). The combined organic phase was dried(MgSO₄), filtered, and concentrated in vacuo to afford Cap-80a as anoff-white solid.(2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methylbutanoic acid wassimilarly elaborated to Cap-80b. Cap-80a: ¹H NMR (DMSO-d₆, δ=2.5 ppm,400 MHz), 12.57 (br s, 1H), 7.64 (d, J=8.3, 0.3H), 7.19 (d, J=8.8,0.7H), 4.44 (dd, J=8.1, 4.6, 0.3H), 4.23 (dd, J=8.7, 4.4, 0.7H),3.56/3.53 (two singlets, 3H), 3.48-3.40 (m, 2H), 2.22-2.10 (m, 1H), 0.85(s, 9H), ˜0.84 (d, 0.9H, overlapped with t-Bu signal), 0.79 (d, J=7,2.1H), 0.02/0.01/0.00 (three overlapping singlets, 6H). LC/MS: Anal.Calcd. for [M+Na]⁺ C₁₃H₂₇NNaO₅Si: 328.16. found 328.46. Cap-80b: ¹H NMR(CDCl₃, δ=7.24 ppm, 400 MHz), 6.00 (br d, J=6.8, 1H), 4.36 (dd, J=7.1,3.1, 1H), 3.87 (dd, J=10.5, 3.0, 1H), 3.67 (s, 3H), 3.58 (dd, J=10.6,4.8, 1H), 2.35 (m, 1H), 1.03 (d, J=7.1, 3H), 0.90 (s, 9H), 0.08 (s, 6H).LC/MS: Anal. Calcd. for [M+Na]⁺ C₁₃H₂₇NNaO₅Si: 328.16. found 328.53. Thecrude products were utilized without further purification.

Cap-81

Prepared according to the protocol described by Falb et al. SyntheticCommunications 1993, 23, 2839.

Cap-82 to Cap-85

Cap-82 to Cap-85 were synthesized from appropriate starting materialsaccording to the procedure described for Cap-51 or Cap-13. The samplesexhibited similar spectral profiles as that of their enantiomers (i.e.,Cap-4, Cap-13, Cap-51 and Cap-52, respectively).

Cap-86

To a mixture of O-methyl-L-threonine (3.0 g, 22.55 mmol), NaOH (0.902 g,22.55 mmol) in H₂O (15 mL) was added C1CO₂Me (1.74 mL, 22.55 mmol)dropwise at 0° C. The mixture was allowed to stir for 12 h and acidifiedto pH 1 using 1N HCl. The aqueous phase was extracted with EtOAc and(2×250 mL) and 10% MeOH in CH₂Cl₂ (250 mL) and the combined organicphases were concentrated under in vacuo to afford a colorless oil (4.18g, 97%) which was of sufficient purity for use in subsequent steps.¹HNMR (400 MHz, CDCl₃) δ 4.19 (s, 1H), 3.92-3.97 (m, 1H), 3.66 (s, 3H),1.17 (d, J=7.7 Hz, 3H). LCMS: Anal. Calcd. for C₇H₁₃NO₅: 191. found: 190(M−H)⁻.

Cap-87

To a mixture of L-homoserine (2.0 g, 9.79 mmol), Na₂CO₃ (2.08 g, 19.59mmol) in H₂O (15 mL) was added C1CO₂Me (0.76 mL, 9.79 mmol) dropwise at0° C. The mixture was allowed to stir for 48 h and acidified to pH 1using 1N HCl. The aqueous phase was extracted with EtOAc and (2×250 mL)and the combined organic phases were concentrated in vacuo to afford acolorless solid (0.719 g, 28%) which was of sufficient purity for use insubsequent steps. ¹HNMR (400 MHz, CDCl₃) δ 4.23 (dd, J=4.5, 9.1 Hz, 1H),3.66 (s, 3H), 3.43-3.49 (m, 2H), 2.08-2.14 (m, 1H), 1.82-1.89 (m, 1H).LCMS: Anal. Calcd. for C₇H₁₃NO₅: 191. found: 192 (M+H)⁺.

Cap-88

A mixture of L-valine (1.0 g, 8.54 mmol), 3-bromopyridine (1.8 mL, 18.7mmol), K₂CO₃ (2.45 g, 17.7 mmol) and CuI (169 mg, 0.887 mmol) in DMSO(10 mL) was heated at 100° C. for 12 h. The reaction mixture was cooledto rt, poured into H₂O (ca. 150 mL) and washed with EtOAc (×2). Theorganic layers were extracted with a small amount of H₂O and thecombined aq phases were acidified to ca. pH 2 with 6N HCl. The volumewas reduced to about one-third and 20 g of cation exchange resin(Strata) was added. The slurry was allowed to stand for 20 min andloaded onto a pad of cation exchange resin (Strata) (ca. 25 g). The padwas washed with H₂O (200 mL), MeOH (200 mL), and then NH₃ (3M in MeOH,2×200 mL). The appropriate fractions was concentrated in vacuo and theresidue (ca. 1.1 g) was dissolved in H₂O, frozen and lyophyllized. Thetitle compound was obtained as a foam (1.02 g, 62%). ¹HNMR (400 MHz,DMSO-d₆) δ 8.00 (s, br, 1H), 7.68-7.71 (m, 1H), 7.01 (s, br, 1H), 6.88(d, J=7.5 Hz, 1H), 5.75 (s, br, 1H), 3.54 (s, 1H), 2.04-2.06 (m, 1H),0.95 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.6 Hz, 3H). LCMS: Anal. Calcd. forC₁₀H₁₄N₂O₂: 194. found: 195 (M+H)⁺.

Cap-89

A mixture of L-valine (1.0 g, 8.54 mmol), 5-bromopyrimidine (4.03 g,17.0 mmol), K₂CO₃ (2.40 g, 17.4 mmol) and CuI (179 mg, 0.94 mmol) inDMSO (10 mL) was heated at 100° C. for 12 h. The reaction mixture wascooled to RT, poured into H₂O (ca. 150 mL) and washed with EtOAc (×2).The organic layers were extracted with a small amount of H₂O and thecombined aq phases were acidified to ca. pH 2 with 6N HCl. The volumewas reduced to about one-third and 20 g of cation exchange resin(Strata) was added. The slurry was allowed to stand for 20 min andloaded onto a pad of cation exchange resin (Strata) (ca. 25 g). The padwas washed with H₂O (200 mL), MeOH (200 mL), and then NH₃ (3M in MeOH,2×200 mL). The appropriate fractions was concentrated in vacuo and theresidue (ca. 1.1 g) was dissolved in H₂O, frozen and lyophyllized. Thetitle compound was obtained as a foam (1.02 g, 62%). ¹HNMR (400 MHz,CD₃OD) showed the mixture to contain valine and the purity could not beestimated. The material was used as is in subsequent reactions. LCMS:Anal. Calcd. for C₉H₁₃N₃O₂: 195. found: 196 (M+H)⁺.

Cap-90

Cap-90 was prepared according to the method described for thepreparation of Cap-1. The crude material was used as is in subsequentsteps. LCMS: Anal. Calcd. for C₁₁H₁₅NO₂: 193. found: 192 (M−H)⁻.

The following caps were prepared according to the method used forpreparation of cap 51 unless noted otherwise:

Cap Structure LCMS Cap-91

LCMS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-92

LCMS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-93

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-94

LCMS: Anal. Calcd. for C₈H₁₁N₃O₄: 213; found: 214 (M + H)⁺. Cap-95

LCMS: Anal. Calcd. for C₁₃H₁₇NO₄: 251; found: 250 (M − H)⁻. Cap-96

LCMS: Anal. Calcd. for C₁₂H₁₅NO₄: 237; found: 236 (M − H)⁻. Cap-97

LCMS: Anal. Calcd. for C₉H₁₅NO₄: 201; found: 200 (M − H)⁻. Cap-98

LCMS: Anal. Calcd. for C₉H₁₅NO₄: 201; found: 202 (M + H)⁺. Cap-99

¹HNMR (400 MHz, CD₃OD) δ 3.88-3.94 (m, 1H), 3.60, 3.61 (s, 3H), 2.80 (m,1H), 2.20 (m 1H), 1.82-1.94 (m, 3H), 1.45-1.71 (m, 2H). Cap-99a

¹HNMR (400 MHz, CD₃OD) δ 3.88-3.94 (m, 1H), 3.60, 3.61 (s, 3H), 2.80 (m,1H), 2.20 (m 1H), 1.82-1.94 (m, 3H), 1.45- 1.71 (m, 2H). Cap-100

LCMS: Anal. Calcd. for C₁₂H₁₄NO₄F: 255; found: 256 (M + H)⁺. Cap-101

LCMS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-102

LCMS: Anal. Calcd. for C₁₁H₁₃NO₄: 223; found: 222 (M − H)⁻. Cap-103

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-104

¹HNMR (400 MHz, CD₃OD) δ 3.60 (s, 3H), 3.50-3.53 (m, 1H), 2.66- 2.69 and2.44-2.49 (m, 1H), 1.91-2.01 (m, 2H), 1.62-1.74 (m, 4H), 1.51- 1.62 (m,2H). Cap-105

¹HNMR (400 MHz, CD₃OD) δ 3.60 (s, 3H), 3.33-3.35 (m, 1H, partiallyobscured by solvent), 2.37-2.41 and 2.16-2.23 (m, 1H), 1.94- 2.01 (m,4H), 1.43- 1.53 (m, 2H), 1.17-1.29 (m, 2H). Cap-106

  Prepared from cis-4- aminocyclohcxane carboxylic acid and acetaldehydeby employing a similar procedure described for the synthesis of Cap-2.The crude HCl salt was passed through MCX (MeOH/H₂O/CH₂Cl₂ wash; 2NNH₃/MeOH elution) to afford an oil, which was dissolved in CH₃CN/H₂O andlyophilized to afford a tan solid. ¹HNMR (400 MHz, CD₃OD) δ 3.16 (q, J =7.3 Hz, 4H), 2.38-2.41 (m, 1H), 2.28-2.31 (m, 2H), 1.79-1.89 (m, 2H),1.74 (app, ddd J = 3.5, 12.5, 15.9 Hz, 2H), 1.46 (app dt J = 4.0, 12.9Hz, 2H), 1.26 (t, J = 7.3 Hz, 6H) Cap-107

LCMS: Anal. Calcd. for C₈H₁₀N₂O₄S: 230; found: 231 (M + H)⁺. Cap-108

LCMS: Anal. Calcd. for C₁₅H₁₇N₃O₄: 303; found: 304 (M + H)⁺. Cap-109

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-110

LCMS: Anal. Calcd. for C₁₀H₁₂N₂O₄: 224; found: 225 (M + H)⁺. Cap-111

LCMS: Anal. Calcd. for C₁₂H₁₆NO₈P: 333; found: 334 (M + H)⁺. Cap-112

LCMS: Anal. Calcd. for C₁₃H₁₄N₂O₄: 262; found: 263 (M + H)⁺. Cap-113

LCMS: Anal. Calcd. for C₁₈H₁₉NO₅: 329; found: 330 (M + H)⁺. Cap-114

¹HNMR (400 MHz, CDCl₃) δ 4.82-4.84 (m, 1H), 4.00-4.05 (m, 2H), 3.77 (s,3H), 2.56 (s, br, 2H) Cap-115

¹HNMR (400 MHz, CDCl₃) δ 5.13 (s, br, 1H), 4.13 (s, br, 1H), 3.69 (s,3H), 2.61 (d, J = 5.0 Hz, 2H), 1.28 (d, J = 9.1 Hz, 3H). Cap-116

¹HNMR (400 MHz, CDCl₃) δ 5.10 (d, J = 8.6 Hz, 1H), 3.74-3.83 (m, 1H),3.69 (s, 3H), 2.54- 2.61 (m, 2H), 1.88 (sept, J = 7.0 Hz, 1H), 0.95 (d,J = 7.0 Hz, 6H).

Cap-117 to Cap-123

For the preparation of Cap-117 to Cap-123 the Boc amino acids wereobtained from commercially sources and were deprotected by treatmentwith 25% TFA in CH₂Cl₂. After complete reaction as judged by LCMS thesolvents were removed in vacuo and the corresponding TFA salt of theamino acid was carbamoylated with methyl chloroformate according to theprocedure described for Cap-51.

Cap Structure LCMS Cap-117

LCMS: Anal. Calcd. for C₁₂H₁₅NO₄: 237; found: 238 (M + H)⁺. Cap-118

LCMS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244 (M + H)⁺. Cap-119

LCMS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244 (M + H)⁺. Cap-120

LCMS: Anal. Calcd. for C₁₀H₁₃NO₄S: 243; found: 244 (M + H)⁺. Cap-121

¹HNMR (400 MHz, CDCl₃) δ 4.06-4.16 (m, 1H), 3.63 (s, 3H), 3.43 (s, 1H),2.82 and 2.66 (s, br, 1H), 1.86- 2.10 (m, 3H), 1.64- 1.76 (m, 2H), 1.44-1.53 (m, 1H). Cap-122

¹HNMR profile is similar to that of its enantiomer, Cap-121 Cap-123

LCMS: Anal. Calcd. for C₂₇H₂₆N₂O₆: 474; found: 475 (M + H)⁺.

Cap-124

The hydrochloride salt of L-threonine tert-butyl ester was carbamoylatedaccording to the procedure for Cap-51. The crude reaction mixture wasacidified with 1N HCl to pH˜1 and the mixture was extracted with EtOAc(2×50 mL). The combined organic phases were concentrated in vacuo togive a colorless oil which solidified on standing. The aqueous layer wasconcentrated in vacuo and the resulting mixture of product and inorganicsalts was triturated with EtOAc-CH₂Cl₂-MeOH (1:1:0.1) and then theorganic phase concentrated in vacuo to give a colorless oil which wasshown by LCMS to be the desired product. Both crops were combined togive 0.52 g of a solid. ¹HNMR (400 MHz, CD₃OD) δ 4.60 (m, 1H), 4.04 (d,J=5.0 Hz, 1H), 1.49 (d, J=6.3 Hz, 3H). LCMS: Anal. Calcd. for C₅H₇NO₄:145. found: 146 (M+H)⁺.

Cap-125

To a suspension of Pd(OH)₂, (20%, 100 mg), aqueous formaldehyde (37% wt,4 ml), acetic acid, (0.5 mL) in methanol (15 mL) was added(S)-4-amino-2-(tert-butoxycarbonylamino)butanoic acid (1 g, 4.48 mmol).The reaction was purged several times with hydrogen and was stirredovernight with an hydrogen balloon room temp. The reaction mixture wasfiltered through a pad of diatomaceous earth (Celite®), and the volatilecomponent was removed in vacuo. The resulting crude material was used asis for the next step. LC/MS: Anal. Calcd. for C₁₁H₂₂N₂O₄: 246. found:247 (M+H)⁺.

Cap-126

This procedure is a modification of that used to prepare Cap-51. To asuspension of 3-methyl-L-histidine (0.80 g, 4.70 mmol) in THF (10 mL)and H₂O (10 mL) at 0° C. was added NaHCO₃ (0.88 g, 10.5 mmol). Theresulting mixture was treated with ClCO₂Me (0.40 mL, 5.20 mmol) and themixture allowed to stir at 0° C. After stirring for ca. 2 h LCMS showedno starting material remaining. The reaction was acidified to pH 2 with6 N HCl.

The solvents were removed in vacuo and the residue was suspended in 20mL of 20% MeOH in CH₂Cl₂. The mixture was filtered and concentrated togive a light yellow foam (1.21 g,). LCMS and ¹H NMR showed the materialto be a 9:1 mixture of the methyl ester and the desired product. Thismaterial was taken up in THF (10 mL) and H₂O (10 mL), cooled to 0° C.and LiOH (249.1 mg, 10.4 mmol) was added. After stirring ca. 1 h LCMSshowed no ester remaining. Therefore the mixture was acidified with 6NHCl and the solvents removed in vacuo. LCMS and ¹H NMR confirm theabsence of the ester. The title compound was obtained as its HCl saltcontaminated with inorganic salts (1.91 g, >100%). The compound was usedas is in subsequent steps without further purification. ¹HNMR (400 MHz,CD₃OD) δ 8.84, (s, 1H), 7.35 (s, 1H), 4.52 (dd, J=5.0, 9.1 Hz, 1H), 3.89(s, 3H), 3.62 (s, 3H), 3.35 (dd, J=4.5, 15.6 Hz, 1H, partially obscuredby solvent), 3.12 (dd, J=9.0, 15.6 Hz, 1H). LCMS: Anal. Calcd. forC₉H₁₃N₃O₄: 227.09. found: 228.09 (M+H)⁺.

Cap-127

Cap-127 was prepared according to the method for Cap-126 above startingfrom (S)-2-amino-3-(1-methyl-1H-imidazol-4-yl)propanoic acid (1.11 g,6.56 mmol), NaHCO₃ (1.21 g, 14.4 mmol) and ClCO₂Me (0.56 mL, 7.28 mmol).The title compound was obtained as its HCl salt (1.79 g, >100%)contaminated with inorganic salts. LCMS and ¹H NMR showed the presenceof ca. 5% of the methyl ester. The crude mixture was used as is withoutfurther purification. ¹HNMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.35 (s,1H), 4.48 (dd, J=5.0, 8.6 Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (m,1H), 3.08 (m, 1H); LCMS: Anal. Calcd. for C₉H₁₃N₃O₄: 227.09. found: 228(M+H)⁺.

Preparation of Cap-128

Step 1. Preparation of (S)-benzyl2-(tert-butoxycarbonylamino)pent-4-ynoate (cj-27b)

To a solution of cj-27a (1.01 g, 4.74 mmol), DMAP (58 mg, 0.475 mmol)and iPr₂NEt (1.7 mL, 9.8 mmol) in CH₂Cl₂ (100 mL) at 0° C. was addedCbz-Cl (0.68 mL, 4.83 mmol). The solution was allowed to stir for 4 h at0° C., washed (1N KHSO₄, brine), dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography (TLC 6:1 hex:EtOAc) to give the title compound (1.30 g,91%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃) δ 7.35 (s, 5H), 5.35 (d,br, J=8.1 Hz, 1H), 5.23 (d, J=12.2 Hz, 1H), 5.17 (d, J=12.2 Hz, 1H),4.48-4.53 (m, 1H), 2.68-2.81 (m, 2H), 2.00 (t, J=2.5 Hz, 1H), 1.44 (s,9H). LCMS: Anal. Calcd. for C₁₇H₂₁NO₄: 303. found: 304 (M+H)⁺.

Step 2. Preparation of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate(cj-28)

To a mixture of (S)-benzyl 2-(tert-butoxycarbonylamino)pent-4-ynoate(0.50 g, 1.65 mmol), sodium ascorbate (0.036 g, 0.18 mmol), CuSO₄-5H₂O(0.022 g, 0.09 mmol) and NaN₃ (0.13 g, 2.1 mmol) in DMF-H₂O (5 mL, 4:1)at rt was added BnBr (0.24 mL, 2.02 mmol) and the mixture was warmed to65° C. After 5 h LCMS indicated low conversion. A further portion ofNaN₃ (100 mg) was added and heating was continued for 12 h. The reactionwas poured into EtOAc and H₂O and shaken. The layers were separated andthe aqueous layer extracted 3× with EtOAc and the combined organicphases washed (H₂O×3, brine), dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by flash (Biotage, 40+M 0-5% MeOHin CH₂Cl₂; TLC 3% MeOH in CH₂Cl₂) to afford a light yellow oil whichsolidified on standing (748.3 mg, 104%). The NMR was consistent with thedesired product but suggests the presence of DMF. The material was usedas is without further purification. ¹HNMR (400 MHz, DMSO-d₆) δ 7.84 (s,1H), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.07 (s, 2H), 4.25 (m, 1H), 3.16(dd, J=1.0, 5.3 Hz, 1H), 3.06 (dd, J=5.3, 14.7 Hz), 2.96 (dd, J=9.1,14.7 Hz, 1H), 1.31 (s, 9H).

LCMS: Anal. Calcd. for C₂₄H₂₈N₄O₄: 436. found: 437 (M+H)⁺.

Step 3. Preparation of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate(cj-29)

A solution of (S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(tert-butoxycarbonylamino)propanoate(0.52 g, 1.15 mmol) in CH₂Cl₂ was added TFA (4 mL). The mixture wasallowed to stir at room temperature for 2 h. The mixture wasconcentrated in vacuo to give a colorless oil which solidified onstanding. This material was dissolved in THF—H₂O and cooled to 0° C.Solid NaHCO₃ (0.25 g, 3.00 mmol) was added followed by ClCO₂Me (0.25 mL,3.25 mmol). After stirring for 1.5 h the mixture was acidified to pH-2with 6N HCl and then poured into H₂O-EtOAc. The layers were separatedand the aq phase extracted 2× with EtOAc. The combined org layers werewashed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated in vacuoto give a colorless oil (505.8 mg, 111%, NMR suggested the presence ofan unidentified impurity) which solidified while standing on the pump.The material was used as is without further purification. ¹HNMR (400MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.27-7.32 (m,10H), 5.54 (s, 2H), 5.10 (d, J=12.7 Hz, 1H), 5.06 (d, J=12.7 Hz, 1H),4.32-4.37 (m, 1H), 3.49 (s, 3H), 3.09 (dd, J=5.6, 14.7 Hz, 1H), 2.98(dd, J=9.6, 14.7 Hz, 1H). LCMS: Anal. Calcd. for C₂₁H₂₂N₄O₄: 394. found:395 (M+H)⁺.

Step 4. Preparation of(S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid(Cap-128)

(S)-benzyl3-(1-benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate(502 mg, 1.11 mmol) was hydrogenated in the presence of Pd—C (82 mg) inMeOH (5 mL) at atmospheric pressure for 12 h. The mixture was filteredthrough diatomaceous earth (Celite®) and concentrated in vacuo.(S)-2-(methoxycarbonylamino)-3-(1H-1,2,3-triazol-4-yl)propanoic acid wasobtained as a colorless gum (266 mg, 111%) which was contaminated withca. 10% of the methyl ester. The material was used as is without furtherpurification. ¹HNMR (400 MHz, DMSO-d₆) δ 12.78 (s, br, 1H), 7.59 (s,1H), 7.50 (d, J=8.0 Hz, 1H), 4.19-4.24 (m, 1H), 3.49 (s, 3H), 3.12 (dd,J=4.8 Hz, 14.9 Hz, 1H), 2.96 (dd, J=9.9, 15.0 Hz, 1H). LCMS: Anal.Calcd. for C₇H₁₀N₄O₄: 214. found: 215 (M+H)⁺.

Preparation of Cap-129

Step 1. Preparation of(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (cj-31)

A suspension of (S)-benzyl 2-oxooxetan-3-ylcarbamate (0.67 g, 3.03mmol), and pyrazole (0.22 g, 3.29 mmol) in CH₃CN (12 mL) was heated at50° C. for 24 h. The mixture was cooled to rt overnight and the solidfiltered to afford(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (330.1mg). The filtrate was concentrated in vacuo and then triturated with asmall amount of CH₃CN (ca. 4 mL) to afford a second crop (43.5 mg).Total yield 370.4 mg (44%). m.p. 165.5-168° C. lit m.p. 168.5-169.5[Vederas et al. J. Am. Chem. Soc. 1985, 107, 7105]. ¹HNMR (400 MHz,CD₃OD) δ 7.51 (d, J=2.0, 1H), 7.48 (s, J=1.5 Hz, 1H), 7.24-7.34 (m, 5H),6.23 m, 1H), 5.05 (d, 12.7H, 1H), 5.03 (d, J=12.7 Hz, 1H), 4.59-4.66 (m,2H), 4.42-4.49 (m, 1H). LCMS: Anal. Calcd. for C₁₄H₁₅N₃O₄: 289. found:290 (M+H)⁺.

Step 2. Preparation of(S)-2-(methoxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (Cap 129)

(S)-2-(benzyloxycarbonylamino)-3-(1H-pyrazol-1-yl)propanoic acid (0.20g, 0.70 mmol) was hydrogenated in the presence of Pd—C (45 mg) in MeOH(5 mL) at atmospheric pressure for 2 h. The product appeared to beinsoluble in MeOH, therefore the reaction mixture was diluted with 5 mLH₂O and a few drops of 6N HCl. The homogeneous solution was filteredthrough diatomaceous earth (Celite®), and the MeOH removed in vacuo. Theremaining solution was frozen and lyophyllized to give a yellow foam(188.9 mg). This material was suspended in THF—H₂O (1:1, 10 mL) and thencooled to 0° C. To the cold mixture was added NaHCO₃ (146.0 mg, 1.74mmol) carefully (evolution of CO₂). After gas evolution had ceased (ca.15 min) ClCO₂Me (0.06 mL, 0.78 mmol) was added dropwise. The mixture wasallowed to stir for 2 h and was acidified to pH˜2 with 6N HCl and pouredinto EtOAc. The layers were separated and the aqueous phase extractedwith EtOAC (×5). The combined organic layers were washed (brine), dried(Na₂SO₄), filtered, and concentrated to give the title compound as acolorless solid (117.8 mg, 79%). ¹HNMR (400 MHz, DMSO-d₆) δ 13.04 (s,1H), 7.63 (d, J=2.6 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.44 (d, J=1.5 Hz,1H), 6.19 (app t, J=2.0 Hz, 1H), 4.47 (dd, J=3.0, 12.9 Hz, 1H),4.29-4.41 (m, 2H), 3.48 (s, 3H). LCMS: Anal. Calcd. for C₈H₁₁N₃O₄: 213.found: 214 (M+H)⁺.

Cap-130

Cap-130 was prepared by acylation of commercially available(R)-phenylglycine analgous to the procedure given in: Calmes, M.;Daunis, J.; Jacquier, R.; Verducci, J. Tetrahedron, 1987, 43(10), 2285.

Cap-131

Step A:

Dimethylcarbamoyl chloride (0.92 mL, 10 mmol) was added slowly to asolution of (S)-benzyl 2-amino-3-methylbutanoate hydrochloride (2.44 g;10 mmol) and Hunig's base (3.67 mL, 21 mmol) in THF (50 mL). Theresulting white suspension was stirred at room temperature overnight (16hours) and concentrated under reduced pressure. The residue waspartitioned between ethyl acetate and water. The organic layer waswashed with brine, dried (MgSO₄), filtered, and concentrated underreduced pressure. The resulting yellow oil was purified by flashchromatography, eluting with ethyl acetate:hexanes (1:1). Collectedfractions were concentrated under vacuum providing 2.35 g (85%) of clearoil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.84 (d, J=6.95 Hz, 3H), 0.89 (d,J=6.59 Hz, 3H), 1.98-2.15 (m, 1H), 2.80 (s, 6H), 5.01-5.09 (m, J=12.44Hz, 1H), 5.13 (d, J=12.44 Hz, 1H), 6.22 (d, J=8.05 Hz, 1H), 7.26-7.42(m, 5H). LC (Cond. 1): RT=1.76 min; MS: Anal. Calcd. for [M+H]⁺C₁₆H₂₂N₂O₃: 279.17. found 279.03.

Step B:

To a MeOH (50 mL) solution of the intermediate prepared above (2.35 g;8.45 mmol) was added Pd/C (10%; 200 mg) and the resulting blacksuspension was flushed with N₂ (3×) and placed under 1 atm of H₂. Themixture was stirred at room temperature overnight and filtered though amicrofiber filter to remove the catalyst. The resulting clear solutionwas then concentrated under reduced pressure to obtain 1.43 g (89%) ofCap-131 as a white foam, which was used without further purification. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 0.87 (d, J=4.27 Hz, 3H), 0.88 (d, J=3.97Hz, 3H), 1.93-2.11 (m, 1H), 2.80 (s, 6H), 3.90 (dd, J=8.39, 6.87 Hz,1H), 5.93 (d, J=8.54 Hz, 1H), 12.36 (s, 1H). LC (Cond. 1): RT=0.33 min;MS: Anal. Calcd. for [M+H]⁺ C₈H₁₇N₂O₃: 189.12. found 189.04.

Cap-132

Cap-132 was prepared from (S)-benzyl 2-aminopropanoate hydrochlorideaccording to the method described for Cap-131. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 1.27 (d, J=7.32 Hz, 3H), 2.80 (s, 6H), 4.06 (qt, 1H), 6.36 (d,J=7.32 Hz, 1H), 12.27 (s, 1H). LC (Cond. 1): RT=0.15 min; MS: Anal.Calcd. for [M+H]⁺ C₆H₁₃N₂O₃: 161.09. found 161.00.

Cap-133

Cap-133 was prepared from (S)-tert-butyl 2-amino-3-methylbutanoatehydrochloride and 2-fluoroethyl chloroformate according to the methoddescribed for Cap-47. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.87 (t, J=6.71Hz, 6H), 1.97-2.10 (m, 1H), 3.83 (dd, J=8.39, 5.95 Hz, 1H), 4.14-4.18(m, 1H), 4.20-4.25 (m, 1H), 4.50-4.54 (m, 1H), 4.59-4.65 (m, 1H), 7.51(d, J=8.54 Hz, 1H), 12.54 (s, 1H).

Cap-134

Cap-134 was prepared from (S)-diethyl alanine and methyl chloroformateaccording to the method described for Cap-51. ¹H NMR (500 MHz, DMSO-d₆)δ ppm 0.72-0.89 (m, 6H), 1.15-1.38 (m, 4H), 1.54-1.66 (m, 1H), 3.46-3.63(m, 3H), 4.09 (dd, J=8.85, 5.19 Hz, 1H), 7.24 (d, J=8.85 Hz, 1H), 12.55(s, 1H). LC (Cond. 2): RT=0.66 min; LC/MS: Anal. Calcd. for [M+H]⁺C₉H₁₈NO₄: 204.12. found 204.02.

Cap-135

A solution of D-2-amino-(4-fluorophenyl)acetic acid (338 mg, 2.00 mmol),1N HCl in diethylether (2.0 mL, 2.0 mmol) and formalin (37%, 1 mL) inmethanol (5 mL) was subjected to balloon hydrogenation over 10%palladium on carbon (60 mg) for 16 h at 25° C. The mixture was thenfiltered through Celite to afford the HCl salt of Cap-135 as a whitefoam (316 mg, 80%). ¹H NMR (300 MHz, MeOH-d₄) δ 7.59 (dd, J=8.80, 5.10Hz, 2H), 7.29 (t, J=8.6 Hz, 2H), 5.17 (s, 1H), 3.05 (v br s, 3H), 2.63(v br s, 3H); R_(t)=0.19 min (Cond.-MS-W5); 95% homogenity index; LRMS:Anal. Calcd. for [M+H]⁺ C₁₀H₁₃FNO₂: 198.09. found: 198.10.

Cap-136

To a cooled (−50° C.) suspension of 1-benzyl-1H-imidazole (1.58 g, 10.0mmol) in anhydrous diethyl ether (50 mL) under nitrogen was addedn-butyl lithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) dropwise. Afterbeing stirred for 20 min at −50° C., dry carbon dioxide (passed throughDrierite) was bubbled into the reaction mixture for 10 min before it wasallowed to warm up to 25° C. The heavy precipitate which formed onaddition of carbon dioxide to the reaction mixture was filtered to yielda hygroscopic, white solid which was taken up in water (7 mL), acidifiedto pH=3, cooled, and induced to crystallize with scratching. Filtrationof this precipitate gave a white solid which was suspended in methanol,treated with 1N HCl/diethyl ether (4 mL) and concentrated in vacuo.Lyophilization of the residue from water (5 mL) afforded the HCl salt ofCap-136 as a white solid (817 mg, 40%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.94(d, J=1.5 Hz, 1H), 7.71 (d, J=1.5 Hz, 1H), 7.50-7.31 (m, 5H), 5.77 (s,2H); R_(t)=0.51 min (Cond.-MS-W5); 95% homogenity index; LRMS: Anal.Calc. for [M+H]⁺ C₁₁H₁₂N₂O₂: 203.08. found: 203.11.

Cap-137

Cap-137, Step A

A suspension of 1-chloro-3-cyanoisoquinoline (188 mg, 1.00 mmol;prepared according to the procedure in WO 2003/099274) (188 mg, 1.00mmol), cesium fluoride (303.8 mg, 2.00 mmol),bis(tri-tert-butylphosphine)palladium dichloride (10 mg, 0.02 mmol) and2-(tributylstannyl)furan (378 μL, 1.20 mmol) in anhydrous dioxane (10mL) under nitrogen was heated at 80° C. for 16 h before it was cooled to25° C. and treated with saturated, aqueous potassium fluoride solutionwith vigorous stirring for 1 h. The mixture was partitioned betweenethyl acetate and water and the organic phase was separated, washed withbrine, dried over Na₂SO₄, filtered and concentrated. Purification of theresidue on silica gel (elution with 0% to 30% ethyl acetate/hexanes)afforded Cap-137, step a (230 mg, 105%) as a white solid which wascarried forward directly. R_(t)=1.95 min (Cond.-MS-W2); 90% homogeneityindex; LRMS: Anal. Calc. for [M+H]⁺ C₁₄H₈N₂O: 221.07. found: 221.12.

Cap-137

To a suspension of Cap 137, step a, (110 mg, 0.50 mmol) and sodiumperiodate (438 mg, 2.05 mmol) in carbon tetrachloride (1 mL),acetonitrile (1 mL) and water (1.5 mL) was added ruthenium trichloridehydrate (2 mg, 0.011 mmol). The mixture was stirred at 25° C. for 2 hand then partitioned between dichloromethane and water. The aqueouslayer was separated, extracted twice more with dichloromethane and thecombined dichloromethane extracts were dried over Na₂SO₄, filtered andconcentrated. Trituration of the residue with hexanes afforded Cap-137(55 mg, 55%) as a grayish-colored solid. R_(t)=1.10 min (Cond.-MS-W2);90% homogeneity index; LCMS: Anal. Calc. for [M+H]⁺ C₁₁H₈N₂O₂: 200.08.found: 200.08.

Caps 138 to 158

Synthetic Strategy. Method A.

Cap-138

Cap-138, Step A

To a stirred suspension of 5-hydroxyisoquinoline (prepared according tothe procedure in WO 2003/099274) (2.0 g, 13.8 mmol) andtriphenylphosphine (4.3 g, 16.5 mmol) in dry tetrahydrofuran (20 mL) wasadded dry methanol (0.8 mL) and diethyl azodicarboxylate (3.0 mL, 16.5mmol) portionwise. The mixture was stirred at room temperature for 20 hbefore it was diluted with ethyl acetate and washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was preabsorbed ontosilica gel and chromatographed (elution with 40% ethyl acetate/hexanes)to afford Cap-138, step a (1.00 g, 45%) as a light yellow solid. ¹H NMR(CDCl₃, 500 MHz) δ 9.19 (s, 1H), 8.51 (d, J=6.0 Hz, 1H), 7.99 (d, J=6.0Hz, 1H), 7.52-7.50 (m, 2H), 7.00-6.99 (m, 1H), 4.01 (s, 3H); R_(t)=0.66min (Cond.-D2); 95% homogeneity index; LCMS: Anal. Calc. for [M+H]⁺C₁₀H₁₀NO: 160.08. found 160.1.

Cap-138, Step B

To a stirred solution of Cap 138, step a (2.34 g, 14.7 mmol) inanhydrous dichloromethane (50 mL) at room temperature was addedmeta-chloroperbenzoic acid (77%, 3.42 g, 19.8 mmol) in one portion.After being stirred for 20 h, powdered potassium carbonate (2.0 g) wasadded and the mixture was stirred for 1 h at room temperature before itwas filtered and concentrated in vacuo to afford Cap-138, step b (2.15g, 83%) as a pale, yellow solid which was sufficiently pure to carryforward directly. ¹H NMR (CDCl₃, 400 MHz) δ 8.73 (d, J=1.5 Hz, 1H), 8.11(dd, J=7.3, 1.7 Hz, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H),7.28 (d, J=8.3 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 4.00 (s, 3H); R_(t)=0.92min, (Cond.-D1); 90% homogenity index; LCMS: Anal. Calc. for [M+H]⁺C₁₀H₁₀NO₂: 176.07. found: 176.0.

Cap-138, Step c

To a stirred solution of Cap 138, step b (0.70 g, 4.00 mmol) andtriethylamine (1.1 mL, 8.00 mmol) in dry acetonitrile (20 mL) at roomtemperature under nitrogen was added trimethylsilylcyanide (1.60 mL,12.00 mmol). The mixture was heated at 75° C. for 20 h before it wascooled to room temperature, diluted with ethyl acetate and washed withsaturated sodium bicarbonate solution and brine prior to drying overNa₂SO₄ and solvent concentration. The residue was flash chromatographedon silica gel (gradient elution with 5% ethyl acetate in hexanes to 25%ethyl acetate in hexanes) to afford Cap-138, step c (498.7 mg, 68%) as awhite, crystalline solid along with 223 mg (30%) of additional Cap-138,step c recovered from the filtrate. ¹H NMR (CDCl₃, 500 MHz) δ 8.63 (d,J=5.5 Hz, 1H), 8.26 (d, J=5.5 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.69 (t,J=8.0 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 4.04 (s, 3H); R_(t)=1.75 min,(Cond.-D1); 90% homogeneity index; LCMS: Anal. Calc. for [M+H]⁺C₁₁H₉N₂O: 185.07. found: 185.10.

Cap-138

Cap-138, step c (0.45 g, 2.44 mmol) was treated with 5N sodium hydroxidesolution (10 mL) and the resulting suspension was heated at 85° C. for 4h, cooled to 25° C., diluted with dichloromethane and acidified with 1Nhydrochloric acid. The organic phase was separated, washed with brine,dried over Na₂SO₄, concentrated to ¼ volume and filtered to affordCap-138 (0.44 g, 88.9%) as a yellow solid. ¹H NMR (DMSO-d₆, 400 MHz) δ13.6 (br s, 1H), 8.56 (d, J=6.0 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 8.06(d, J=8.8 Hz, 1H), 7.71-7.67 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.02 (s,3H); R_(t)=0.70 min (Cond.-D1); 95% homogenity index; LCMS: Anal. Calc.for [M+H]⁺ C₁₁H₁₀NO₃: 204.07. found: 204.05.

Synthetic Strategy. Method B (Derived from Tetrahedron Letters, 2001,42, 6707).

Cap-139

Cap-139, Step A

To a thick-walled, screw-top vial containing an argon-degassedsuspension of 1-chloro-6-methoxyisoquinoline (1.2 g, 6.2 mmol; preparedaccording to the procedure in WO 2003/099274), potassium cyanide (0.40g, 6.2 mmol), 1,5-bis(diphenylphosphino)pentane (0.27 g, 0.62 mmol) andpalladium (II) acetate (70 mg, 0.31 mmol) in anhydrous toluene (6 mL)was added N,N,N′,N′-tetramethylethylenediamine (0.29 mL, 2.48 mmol). Thevial was sealed, heated at 150° C. for 22 h and then allowed to cool to25° C. The reaction mixture was diluted with ethyl acetate, washed withwater and brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified on silica gel (gradient elution with 5% ethylacetate/hexanes to 25% ethyl acetate/hexanes) to afford Cap-139, step a(669.7 mg, 59%) as a white solid. ¹H NMR (CDCl₃, 500 MHz) δ 8.54 (d,J=6.0 Hz, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.76 (d, J=5.5 Hz, 1H), 7.41-7.39(m, 1H), 7.13 (d, J=2.0 Hz, 1H), 3.98 (s, 3H); R_(t)=1.66 min(Cond.-D1); 90% homogenity index; LCMS: Anal. Calc. for [M+H]⁺ C₁₁H₉N₂O:185.07. found: 185.2.

Cap-139

Cap-139 was prepared from the basic hydrolysis of Cap-139, step a with5N NaOH according to the procedure described for Cap 138. ¹H NMR (400MHz, DMSO-d₆) δ 13.63 (v br s, 1H), 8.60 (d, J=9.3 Hz, 1H), 8.45 (d,J=5.6 Hz, 1H), 7.95 (d, J=5.9 Hz, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.44 (dd,J=9.3, 2.5 Hz, 1H), 3.95 (s, 3H); R_(t)=0.64 min (Cond.-D1); 90%homogenity index; LCMS: Anal. Calc. for [M+H]⁺ C₁₁H₁₀NO₃: 204.07. found:204.05.

Cap-140

Cap-140, Step A

To a vigorously-stirred mixture of 1,3-dichloro-5-ethoxyisoquinoline(482 mg, 2.00 mmol; prepared according to the procedure in WO2005/051410), palladium (II) acetate (9 mg, 0.04 mmol), sodium carbonate(223 mg, 2.10 mmol) and 1,5-bis(diphenylphosphino)pentane (35 mg, 0.08mmol) in dry dimethylacetamide (2 mL) at 25° C. under nitrogen was addedN,N,N′,N′-tetramethylethylenediamine (60 mL, 0.40 mmol). After 10 min,the mixture was heated to 150° C., and then a stock solution of acetonecyanohydrin (prepared from 457 μL of acetone cyanohydrin in 4.34 mL DMA)was added in 1 mL portions over 18 h using a syringe pump. The mixturewas then partitioned between ethyl acetate and water and the organiclayer was separated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel (gradient elutionwith 10% ethyl acetate in hexanes to 40% ethyl acetate in hexanes) toafford Cap-140, step a (160 mg, 34%) as a yellow solid. R_(t)=2.46 min(Cond.-MS-W2); 90% homogenity index; LCMS: Anal. Calc. for [M+H]⁺C₁₂H₉ClN₂O: 233.05. found: 233.08.

Cap-140

Cap-140 was prepared by the acid hydrolysis of Cap-140, step a with 12NHCl as described in the procedure for the preparation of Cap 141,described below. R_(t)=2.24 min (Cond.-MS-W2); 90% homogenity index;LCMS: Anal. Calc. for [M+H]⁺ C₁₂H₁₁ClNO₃: 252.04. found: 252.02.

Cap-141

Cap-141, Step A

Cap-141, step a was prepared from 1-bromo-3-fluoroisoquinoline (preparedfrom 3-amino-1-bromoisoquinoline using the procedure outlined in J. Med.Chem. 1970, 13, 613) as described in the procedure for the preparationof Cap-140, step a (vide supra). ¹H NMR (500 MHz, CDCl₃) δ 8.35 (d,J=8.5 Hz, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.83 (t, J=7.63 Hz, 1H),7.77-7.73 (m, 1H), 7.55 (s, 1H); R_(t)=1.60 min (Cond.-D1); 90%homogenity index; LCMS: Anal. Calc. for [M+H]⁺ C₁₀H₆FN₂: 173.05. found:172.99.

Cap-141

Cap-141, step a (83 mg, 0.48 mmol) was treated with 12N HCl (3 mL) andthe resulting slurry was heated at 80° C. for 16 h before it was cooledto room temperature and diluted with water (3 mL). The mixture wasstirred for 10 min and then filtered to afford Cap-141 (44.1 mg, 48%) asan off-white solid. The filtrate was diluted with dichloromethane andwashed with brine, dried over Na₂SO₄, and concentrated to affordadditional Cap-141 (29.30 mg, 32%) which was sufficiently pure to becarried forward directly. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.0 (br s, 1H),8.59-8.57 (m, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.88-7.85 (m, 2H), 7.74-7.71(m, 1H); R_(t)=1.33 min (Cond.-D1); 90% homogenity index; LCMS: Anal.Calc. for [M+H]⁺ C₁₀H₇FNO₂: 192.05. found: 191.97.

Cap-142

Cap-142, Step A

Cap-142, step a was prepared from 4-bromoisoquinoline N-oxide asdescribed in the two-step procedure for the preparation of Cap-138,steps b and c. R_(t)=1.45 min (Cond.-MS-W1); 90% homogenity index; LCMS:Anal. Calc. for [M+H]⁺ C₁₀H₆BrN₂: 232.97. found: 233.00.

Cap-142, Step B

To an argon-degassed suspension of Cap-142, step a (116 mg, 0.50 mmol),potassium phosphate tribasic (170 mg, 0.80 mmol), palladium (II) acetate(3.4 mg, 0.015 mmol) and 2-(dicyclohexylphosphino)biphenyl (11 mg, 0.03mmol) in anhydrous toluene (1 mL) was added morpholine (61 μL, 0.70mmol). The mixture was heated at 100° C. for 16 h, cooled to 25° C.,filtered through diatomaceous earth (Celite®) and concentrated.Purification of the residue on silica gel (gradient elution with 10% to70% ethyl acetate in hexanes) afforded Cap-142, step b (38 mg, 32%) as ayellow solid which was carried forward directly. R_(t)=1.26 min(Cond.-MS-W1); 90% homogenity index; LCMS: Anal. Calc. for [M+H]⁺C₁₄H₁₄N₃O: 240.11. found: 240.13.

Cap-142

Cap-142 was prepared from Cap-142, step b with 5N sodium hydroxide asdescribed in the procedure for Cap 138. R_(t)=0.72 min (Cond.-MS-W1);90% homogenity index; LCMS: Anal. Calc. for [M+H]⁺ C₁₄H₁₅N₂O₃: 259.11.found: 259.08.

Cap-143

Cap-143, Step A

To a stirred solution of 3-amino-1-bromoisoquinoline (444 mg, 2.00 mmol)in anhydrous dimethylformamide (10 mL) was added sodium hydride (60%,unwashed, 96 mg, 2.4 mmol) in one portion. The mixture was stirred at25° C. for 5 min before 2-bromoethyl ether (90%, 250 μL, 2.00 mmol) wasadded. This mixture was stirred further at 25° C. for 5 h and at 75° C.for 72 h before it was cooled to 25° C., quenched with saturatedammonium chloride solution and diluted with ethyl acetate. The organiclayer was separated, washed with water and brine, dried over Na₂SO₄,filtered and concentrated. Purification of the residue on silica gel(gradient elution with 0% to 70% ethyl acetate in hexanes) affordedCap-143, step a (180 mg, 31%) as a yellow solid. R_(t)=1.75 min(Cond.-MS-W1); 90% homogenity index; LCMS: Anal. Calc. for [M+H]⁺C₁₃H₁₄BrN₂O: 293.03. found: 293.04.

Cap-143

To a cold (−60° C.) solution of Cap-143, step a (154 mg, 0.527 mmol) inanhydrous tetrahydrofuran (5 mL) was added a solution of n-butyllithiumin hexanes (2.5 M, 0.25 mL, 0.633 mmol). After 10 min, dry carbondioxide was bubbled into the reaction mixture for 10 min before it wasquenched with 1N HCl and allowed to warm to 25° C. The mixture was thenextracted with dichloromethane (3×30 mL) and the combined organicextracts were concentrated in vacuo. Purification of the residue byreverse phase HPLC (MeOH/water/TFA) afforded Cap-143 (16 mg, 12%).R_(t)=1.10 min (Cond.-MS-W1); 90% homogenity index; LCMS: Anal. Calc.for [M+H]⁺ C₁₄H₁₅N₂O₃: 259.11. found: 259.08.

Cap-144

Cap-144, Step A

1,3-Dichloroisoquinoline (2.75 g, 13.89 mmol) was added in smallportions to a cold (0° C.) solution of fuming nitric acid (10 mL) andconcentrated sulfuric acid (10 mL). The mixture was stirred at 0° C. for0.5 h before it was gradually warmed to 25° C. where it stirred for 16h. The mixture was then poured into a beaker containing chopped ice andwater and the resulting suspension was stirred for 1 h at 0° C. beforeit was filtered to afford Cap-144, step a (2.73 g, 81%) as a yellowsolid which was used directly. R_(t)=2.01 min (Cond.-D1); 95% homogenityindex; LCMS: Anal. Calc. for [M+H]⁺ C₉H₅Cl₂N₂O₂: 242.97. found: 242.92.

Cap-144, Step B

Cap-144, step a (0.30 g, 1.23 mmol) was taken up in methanol (60 mL) andtreated with platinum oxide (30 mg), and the suspension was subjected toParr hydrogenation at 7 psi H₂ for 1.5 h before formalin (5 mL) andadditional platinum oxide (30 mg) were added. The suspension wasresubjected to Parr hydrogenation at 45 psi H₂ for 13 h before it wassuction-filtered through diatomaceous earth (Celite®) and concentrateddown to ¼ volume. Suction-filtration of the ensuing precipitate affordedthe title compound as a yellow solid which was flash chromatographed onsilica gel (gradient elution with 5% ethyl acetate in hexanes to 25%ethyl acetate in hexanes) to afford Cap-144, step b (231 mg, 78%) as apale, yellow solid. R_(t)=2.36 min (Cond.-D1); 95% homogenity index; ¹HNMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.57-7.53(m, 1H), 7.30 (d, J=7.3 Hz, 1H), 2.88 (s, 6H); LCMS: Anal. Calc. for[M+H]⁺ C₁₁H₁₁Cl₂N₂: 241.03. found: 241.02. HRMS: Anal. Calc. for [M+H]⁺C₁₁H₁₁Cl₂N₂: 241.0299. found: 241.0296.

Cap-144, Step c

Cap-144, step c was prepared from Cap-144, step b according to theprocedure described for the preparation of Cap-139, step a. R_(t)=2.19min (Cond.-D1); 95% homogenity index; LCMS: Anal. Calc. for [M+H]⁺C₁₂H₁₁ClN₃: 232.06. found: 232.03. HRMS: Anal. Calc. for [M+H]⁺C₁₂H₁₁ClN₃: 232.0642. found: 232.0631.

Cap-144

Cap-144 was prepared according to the procedure described for Cap-141.R_(t)=2.36 min (Cond.-D1); 90%; LCMS: Anal. Calc. for [M+H]⁺C₁₂H₁₂ClN₂O₂: 238.01. found: 238.09.

Caps-145 to -162

Caps-145 to 162 were prepared from the appropriate 1-chloroisoquinolinesaccording to the procedure described for the preparation of Cap-138(Method A) or Cap-139 (Method B) unless noted otherwise as outlinedbelow.

R_(t) (LC- Cond.); % homogeneity index; Cap # Cap Method Hydrolysis MSdata Cap-145

  Prepared from commercially available 1,3- dichloroisoquinoline B 12NHCl 1.14 min (Cond.-MS-W1); 90%; LCMS: Anal. Calc. for [M + H]⁺C₁₀H₇ClNO₂: 208.02; found: 208.00. Cap-146

  Prepared from commercially available 3-hydroxyisoquinoline A 5N NaOH1.40 min (Cond.-D1); 95%; LCMS: Anal. Calc. for [M + H]⁺ C₁₁H₁₀NO₃:204.07; found: 204.06. Cap-147

  Prepared from commercially available 1-chloro-4- hydroxyisoquinoline B5N NaOH 0.87 min (Cond.-D1); 95%; LCMS: Anal. Calc. for [M + H]⁺C₁₁H₁₀NO₃: 204.07; found: 204.05. Cap-148

  Prepared from commercially available 7-hydroxyisoquinoline A 5N NaOH0.70 min (Cond.-D1); 95%; LCMS: Anal. Calc. for [M + H]⁺ C₁₁H₁₀NO₃:204.07; found: 204.05. Cap-149

  Prepared from commercially available 5-hydroxyisoquinoline A 5N NaOH0.70 min (Cond.-D1); 95%; LCMS: Anal. Calc. for [M + H]⁺ C₁₁H₁₀NO₃:204.07; found: 204.05. Cap-150

  Prepared from 8-methoxy-1- chloroisoquinoline, which can besynthesized following the procedure in WO 2003/099274 A 12N HCl 0.26 min(Cond.-D1); 95%; LCMS: Anal. Calc. for [M + H]⁺ C₁₁H₁₀NO₃: 204.07;found: 204.04. Cap-151

  Prepared from 5-methoxy-1,3- dichloroisoquinoline, which can besynthesized following the procedure in WO 2005/051410. B 12N HCl 1.78min (Cond.-D1); 90%; LCMS: Anal. Calc. for [M + H]⁺ C₁₁H₉ClNO₃: 238.03;found: 238.09. Cap-152

  Prepared from commercially available 6-methoxy-1,3-dichloroisoquinoline B 12N HCl 1.65 min (Cond.-D1); 95%; LCMS: Anal.Calc. for [M + H]⁺ C₁₁H₉ClNO₃: 238.00; found: 238.09. Cap-153

  Prepared from 4- bromoisoquinoline, which can be synthesized followingthe procedure in WO 2003/062241 A 6N HCl 1.18 min (Cond.-MS- W1); 95%;LCMS: Anal. Calc. for [M + H]⁺ C₁₀H₇BrNO₂: 251.97; found: 251.95.Cap-154

  Prepared from 7-fluoro-1- chloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.28 min (Cond.-MS-W1); 90%; LCMS: Anal. Calc. for [M + H]⁺ C₁₀H₇FNO₂: 192.05; found:192.03. Cap-155

  Prepared from 1,7- dichloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.59 min (Cond.-MS-W1); 90%; LCMS: Anal. Calc. for [M + H]⁺ C₁₀H₇ClNO₂: 208.02; found:208.00. Cap-156

  Prepared from 1,6- dichloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.60 min (Cond.-MS-W1); 90%; LCMS: Anal. Calc. for [M + H]⁺ C₁₀H₇ClNO₂: 208.02; found:208.03. Cap-157

  Prepared from 1,4- dichloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/062241 B 12N HCl 1.49 min (Cond.-D1);95%; LCMS: Anal. Calc. for [M + H]⁺ C₁₀H₁₇ClNO: 208.02; found: 208.00.Cap-158

  Prepared from 1,5- dichloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.69 min (Cond.-MS-W1); 90%; LCMS: Anal. Calc. for [M + H]⁺ C₁₀H₇ClNO₂: 208.02; found:208.01. Cap-159

  Prepared from 5-fluoro-1- chloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.41 min (Cond.-MS-W1); 90%; LCMS: Anal. Calc. for [M + H]⁺ C₁₀H₇FNO₂: 192.05; found:192.03. Cap-160

  Prepared from 6-fluoro-1- chloroisoquinoline, which can be synthesizedfollowing the procedure in WO 2003/099274 B 5N NaOH 0.30 min (Cond.-MS-W1); 90%; LCMS: Anal. Calc. for [M + H]⁺ C₁₀H₇FNO₂: 192.05; found:192.03. Cap-161

  Prepared from 4-bromoquinoline- 2-carboxylic acid and dimethylamine(DMSO, 100° C.) — — 0.70 min (Cond. D1); 95%; LCMS: Anal. Calc. for [M +H]⁺ C₁₂H₁₃N₂O₂: 217.10; found: 217.06. Cap-162

  Prepared from m-anisidine following the procedure described in J.Hetero. Chem. 1993, 17 and Heterocycles, 2003, 60, 953. — — 0.65 min(Cond.-M3); 95%; LCMS: Anal. Calc. for [M + H]⁺ C₁₁H₁₀NO₃: 204.07;found: 203.94.

Cap-163

To a solution of 2-ketobutyric acid (1.0 g, 9.8 mmol) in diethylether(25 ml) was added phenylmagnesium bromide (22 ml, 1M in THF) dropwise.The reaction was stirred at ˜25° C. under nitrogen for 17.5 h. Thereaction was acidified with 1N HCl and the product was extracted withethyl acetate (3×100 ml). The combined organic layer was washed withwater followed by brine and dried over MgSO₄. After concentration invacuo, a white solid was obtained. The solid was recrystallized fromhexanes/ethyl acetate to afford Cap-163 as white needles (883.5 mg). ¹HNMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): 12.71 (br s, 1H), 7.54-7.52 (m, 2H),7.34-7.31 (m, 2H), 7.26-7.23 (m, 1H), 5.52-5.39 (br s, 1H), 2.11 (m,1H), 1.88 (m, 1H), 0.79 (app t, J=7.4 Hz, 3H).

Cap-164

A mixture of 2-amino-2-phenylbutyric acid (1.5 g, 8.4 mmol),formaldehyde (14 mL, 37% in water), 1N HCl (10 mL) and 10% Pd/C (0.5 mg)in MeOH (40 mL) was exposed to H₂ at 50 psi in a Parr bottle for 42 h.The reaction was filtered over Celite and concentrated in vacuo, theresidue was taken up in MeOH (36 mL) and the product was purified with areverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA salt of Cap-164 as awhite solid (1.7 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500 MHz) 7.54-7.47 (m,5H), 2.63 (m, 1H), 2.55 (s, 6H), 2.31 (m, 1H), 0.95 (app t, J=7.3 Hz,3H).

Cap-165

To a mixture of 2-amino-2-indanecarboxylic acid (258.6 mg, 1.46 mmol)and formic acid (0.6 ml, 15.9 mmol) in 1,2-dichloroethane (7 ml) wasadded formaldehyde (0.6 ml, 37% in water). The mixture was stirred at˜25° C. for 15 min then heated at 70° C. for 8 h. The volatile componentwas removed in vacuo, and the residue was dissolved in DMF (14 mL) andpurified by a reverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA saltof Cap-165 as a viscous oil (120.2 mg). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 500MHz): 7.29-7.21 (m, 4H), 3.61 (d, J=17.4 Hz, 2H), 3.50 (d, J=17.4 Hz,2H), 2.75 (s, 6H). LC/MS: Anal. Calcd. for [M+H]⁺ C₁₂H₁₆NO₂: 206.12.found: 206.07.

Cap-166a and -166b

Caps-166a and -166b were prepared from (1S,4S)-(+)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (2HBr) according to themethod described for the synthesis of Cap-7a and Cap-7b, with theexception that the benzyl ester intermediate was separated using asemi-prep Chrialcel OJ column, 20×250 mm, 10 μm eluting with 85:15heptane/ethanol mixture at 10 mL/min elution rate for 25 min. Cap-166b:¹HNMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): 7.45 (d, J=7.3 Hz, 2H), 7.27-7.19(m, 3H), 4.09 (s, 1H), 3.34 (app br s, 1H), 3.16 (app br s, 1H), 2.83(d, J=10.1 Hz, 1H), 2.71 (m, 2H), 2.46 (m, 1H), 2.27 (s, 3H), 1.77 (d,J=9.8 Hz, 1H), 1.63 (d, J=9.8 Hz, 1H). LC/MS: Anal. Calcd. for [M+H]⁺C₁₄H₁₉N₂O₂: 247.14. found: 247.11.

Cap-167

A solution of racemic Boc-1,3-dihydro-2H-isoindole carboxylic acid (1.0g, 3.8 mmol) in 20% TFA/CH₂Cl₂ was stirred at ˜25° C. for 4 h. All thevolatile component was removed in vacuo. A mixture of the resultantcrude material, formaldehyde (15 mL, 37% in water), 1N HCl (10 mL) and10% Pd/C (10 mg) in MeOH was exposed to H₂ (40 PSI) in a Parr bottle for23 h. The reaction mixture was filtered over Celite and concentrated invacuo to afford Cap-167 as a yellow foam (873.5 mg). ¹H NMR (DMSO-d₆,δ=2.5 ppm, 500 MHz) 7.59-7.38 (m, 4H), 5.59 (s, 1H), 4.84 (d, J=14 Hz,1H), 4.50 (d, J=14.1 Hz, 1H), 3.07 (s, 3H). LC/MS: Anal. Calcd. for[M+H]⁺ C₁₀H₁₂NO₂: 178.09. found: 178.65.

Cap-168

Racemic Cap-168 was prepared from racemic Boc-aminoindane-1-carboxylicacid according to the procedure described for the preparation ofCap-167. The crude material was employed as such.

Cap-169

A mixture of 2-amino-2-phenylpropanoic acid hydrochloride (5.0 g, 2.5mmol), formaldehyde (15 ml, 37% in water), 1N HCl (15 ml), and 10% Pd/C(1.32 g) in MeOH (60 mL) was placed in a Parr bottle and shaken underhydrogen (55 PSI) for 4 days. The reaction mixture was filtered overCelite and concentrated in vacuo. The residue was taken up in MeOH andpurified by reverse phase prep-HPLC (MeOH/water/TFA) to afford the TFAsalt of Cap-169 as a viscous semi-solid (2.1 g). ¹H NMR (CDCl₃, δ=7.26ppm, 500 MHz): 7.58-7.52 (m, 2H), 7.39-7.33 (m, 3H), 2.86 (br s, 3H),2.47 (br s, 3H), 1.93 (s, 3H). LC/MS: Anal. Calcd. for [M+H]⁺ C₁₁H₁₆NO₂:194.12. found: 194.12.

Cap-170

To (S)-2-amino-2-(tetrahydro-2H-pyran-4-yl)acetic acid (505 mg; 3.18mmol; obtained from Astatech) in water (15 ml) was added sodiumcarbonate (673 mg; 6.35 mmol), and the resultant mixture was cooled to0° C. and then methyl chloroformate (0.26 ml; 3.33 mmol) was addeddropwise over 5 minutes. The reaction was allowed to stir for 18 hourswhile allowing the bath to thaw to ambient temperature. The reactionmixture was then partitioned between 1N HCl and ethyl acetate. Theorganic layer was removed and the aqueous layer was further extractedwith 2 additional portions of ethyl acetate. The combined organic layerswere washed with brine, dried over magnesium sulfate, filtered andconcentrated in vacuo to afford Cap-170a colorless residue. ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.65 (1H, br s), 7.44 (1H, d, J=8.24 Hz), 3.77-3.95(3H, m), 3.54 (3H, s), 3.11-3.26 (2H, m), 1.82-1.95 (1H, m), 1.41-1.55(2H, m), 1.21-1.39 (2H, m); LC/MS: Anal. Calcd. for [M+H]⁺ C₉H₁₆NO₅:218.1. found 218.1.

Cap-171

A solution of methyl2-(benzyloxycarbonylamino)-2-(oxetan-3-ylidene)acetate (200 mg, 0.721mmol; Il Farmaco (2001), 56, 609-613) in ethyl acetate (7 ml) and CH₂Cl₂(4.00 ml) was degassed by bubbling nitrogen for 10 min. Dimethyldicarbonate (0.116 ml, 1.082 mmol) and Pd/C (20 mg, 0.019 mmol) werethen added, the reaction mixture was fitted with a hydrogen balloon andallowed to stir at ambient temperature overnight at which time TLC (95:5CH₂Cl₂/MeOH: visulalized with stain made from 1 g Ce(NH₄)₂SO₄, 6 gammonium molybdate, 6 ml sulfuric acid, and 100 ml water) indicatedcomplete conversion. The reaction was filtered through celite andconcentrated. The residue was purified via Biotage (load withdichloromethane on 25 samplet; elute on 25S column with dichloromethanefor 3CV then 0 to 5% MeOH/dichloromethane over 250 ml then hold at 5%MeOH/dichloromethane for 250 ml; 9 ml fractions). Collected fractionscontaining desired material and concentrated to 120 mg (81%) of methyl2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless oil. ¹HNMR (500 MHz, CHLOROFORM-D) δ ppm 3.29-3.40 (m, J=6.71 Hz, 1H) 3.70 (s,3H) 3.74 (s, 3H) 4.55 (t, J=6.41 Hz, 1H) 4.58-4.68 (m, 2H) 4.67-4.78 (m,2H) 5.31 (br s, 1H). LC/MS: Anal. Calcd. for [M+H]⁺ C₈H₁₄NO₅: 204.2.found 204.0.

To methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246mmol) in THF (2 mL) and water (0.5 mL) was added lithium hydroxidemonohydrate (10.33 mg, 0.246 mmol). The resultant solution was allowedto stir overnite at ambient temperature. TLC (1:1 EA/Hex; Hanessianstain [1 g Ce(NH₄)₂SO₄, 6 g ammonium molybdate, 6 ml sulfuric acid, and100 ml water]) indicated ˜10% starting material remaining Added anadditional 3 mg LiOH and allowed to stir overnight at which time TLCshowed no starting material remaining Concentrated in vacuo and placedon high vac overnite providing 55 mg lithium2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless solid. ¹HNMR (500 MHz, MeOD) δ ppm 3.39-3.47 (m, 1H) 3.67 (s, 3H) 4.28 (d, J=7.93Hz, 1H) 4.64 (t, J=6.26 Hz, 1H) 4.68 (t, J=7.02 Hz, 1H) 4.73 (d, J=7.63Hz, 2H).

Cap-172

Cap-172, Step A

The following diazotization step was adapted from Barton, A.;Breukelman, S. P.; Kaye, P. T.; Meakins, G. D.; Morgan, D. J. J. C. S.Perkin Trans I 1982, 159-164: A solution of NaNO₂ (166 mg, 2.4 mmol) inwater (0.6 mL) was added slowly to a stirred, cold (0° C.) solution ofmethyl 2-amino-5-ethyl-1,3-thiazole-4-carboxylate (186 mg, 1.0 mmol),CuSO₄.5H₂O (330 mg, 1.32 mmol), NaCl (260 mg, 4.45 mmol) and H₂SO₄ (5.5mL) in water (7.5 mL). The mixture was stirred at 0° C. for 45 min andallowed to warm up to room temperature where it stirred further for 1 hbefore CuCl (118 mg) was added. This mixture was stirred further at roomtemperature for 16 h before it was diluted with brine and extracted withether twice. The organic layers were combined, dried over MgSO₄ andconcentrated to give methyl 2-chloro-5-ethylthiazole-4-carboxylate (i.e.Cap-172, step a) (175 mg, 85%) as an orange oil (80% pure) which wasused directly in the next reaction. R_(t)=1.99 min (Cond.-MD1); LC/MS:Anal. Calcd. for [M+H]⁺ C₇H₉ClNO₂S: 206.01. found: 206.05.

Cap-172

To a solution of methyl 2-chloro-5-ethylthiazole-4-carboxylate (175 mg)in THF/H₂O/MeOH (20 mL/3 mL/12 mL) was added LiOH (305 mg, 12.76 mmol).The mixture was stirred at room temperature overnight before it wasconcentrated down and neutralized with 1N HCl in ether (25 mL). Theresidue was extracted twice with ethyl acetate and the organic layerswere combined, dried over MgSO₄ and evaporated to yield Cap-172 (60 mg,74%) as a red solid which was used without further purification. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 13.03-13.42 (1H, m), 3.16 (2H, q, J=7.4 Hz),1.23 (3H, t, J=7.5 Hz). R_(t)=1.78 min (Cond.-MD1); LC/MS: Anal. Calcd.for [M+H]⁺ C₆H₇ClNO₂S: 191.99. found: 191.99.

Cap-173

Cap-173, Step A

The following diazotization step was adapted from Barton, A.;Breukelman, S. P.; Kaye, P. T.; Meakins, G. D.; Morgan, D. J. J. C. S.Perkin Trans 11982, 159-164: A solution of NaNO₂ (150 mg, 2.17 mmol) inwater (1.0 mL) was added dropwise to a stirred, cold (0° C.) solution ofmethyl 2-amino-5-ethyl-1,3-thiazole-4-carboxylate (186 mg, 1.0 mmol) in50% H₃PO₂ (3.2 mL). The mixture was stirred at 0° C. for 1 h and allowedto warm up to room temperature where it stirred further for 2 h. Afterrecooling to 0° C., the mixture was treated slowly with a solution ofNaOH (85 mg) in water (10 mL). The mixture was then diluted withsaturated NaHCO₃ solution and extracted twice with ether. The organiclayers were combined, dried over MgSO₄ and concentrated to give methyl5-ethylthiazole-4-carboxylate (i.e. Cap-173, step a) (134 mg, 78%) as anorange oil (85% pure) which was used directly in the next reaction.R_(t)=1.58 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]⁺ C₇H₁₀NO₂S:172.05. found: 172.05.

Cap-173

To a solution of methyl 5-ethylthiazole-4-carboxylate (134 mg) inTHF/H₂O/MeOH (18 mL/2.7 mL/11 mL) was added LiOH (281 mg, 11.74 mmol).The mixture was stirred at room temperature overnight before it wasconcentrated down and neutralized with 1N HCl in ether (25 mL). Theresidue was extracted twice with ethyl acetate and the organic layerswere combined, dried over MgSO₄ and evaporated to yield Cap-173 (90 mg,73%) as an orange solid which was used without further purification. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 12.74-13.04 (1H, m), 3.20 (2H, q, J=7.3Hz), 1.25 (3H, t, J=7.5 Hz). R_(t)=1.27 min (Cond.-MD1); LC/MS: Anal.Calcd. for [M+H]⁺ C₆H₈NO₂S: 158.03. found: 158.04.

Cap-174

Cap-174, Step A

Triflic anhydride (5.0 g, 18.0 mmol) was added dropwise to a cold (0°C.) solution of methyl 3-hydroxypicolinate (2.5 g, 16.3 mmol) and TEA(2.5 mL, 18.0 mmol) in CH₂Cl₂ (80 mL). The mixture was stirred at 0° C.for 1 h before it was allowed to warm up to room temperature where itstirred for an additional 1 h. The mixture was then quenched withsaturated NaHCO₃ solution (40 mL) and the organic layer was separated,washed with brine, dried over MgSO₄ and concentrated to give methyl3-(trifluoromethylsulfonyloxy)picolinate (i.e. Cap-174, step a) (3.38 g,73%) as a dark brown oil (>95% pure) which was used directly withoutfurther purification. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.72-8.79 (1H, m),7.71 (1H, d, J=1.5 Hz), 7.58-7.65 (1H, m), 4.04 (3H, s). R_(t)=1.93 min(Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]⁺ C₈H₇F₃NO₅S: 286.00. found:286.08.

Cap-174

To a solution of methyl 3-(trifluoromethylsulfonyloxy)picolinate (570mg, 2.0 mmol) in DMF (20 mL) was added LiCl (254 mg, 6.0 mmol),tributyl(vinyl)stannane (761 mg, 2.4 mmol) andbis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol). Themixture was heated at 100° C. overnight before a saturated solution ofKF (20 mL) was added to the reaction mixture at room temperature. Thismixture was stirred for 4 h before it was filtered through Celite andthe pad of Celite was washed with ethyl acetate. The aqueous phase ofthe filtrate was then separated and concentrated down in vacuo. Theresidue was treated with 4N HCl in dioxanes (5 mL) and the resultingmixture was extracted with methanol, filtered and evaporated to affordCap-174 (260 mg) as a green solid which was slightly contaminated withinorganic salts but was used without further purification. ¹H NMR (300MHz, DMSO-d₆) δ ppm 8.21 (1H, d, J=3.7 Hz), 7.81-7.90 (1H, m), 7.09 (1H,dd, J=7.7, 4.8 Hz), 6.98 (1H, dd, J=17.9, 11.3 Hz), 5.74 (1H, dd,J=17.9, 1.5 Hz), 5.20 (1H, d, J=11.0 Hz). R_(t)=0.39 min (Cond.-MD1);LC/MS: Anal. Calcd. for [M+H]⁺ C₈H₈NO₂: 150.06. found: 150.07.

Cap-175

Cap-175, Step A

To a solution of methyl 3-(trifluoromethylsulfonyloxy)picolinate (i.e.Cap 173, step a) (570 mg, 2.0 mmol), an intermediate in the preparationof Cap-174, in DMF (20 mL) was added LiCl (254 mg, 6.0 mmol),tributyl(vinyl)stannane (761 mg, 2.4 mmol) andbis(triphenylphosphine)palladium dichloride (42 mg, 0.06 mmol). Themixture was heated at 100° C. for 4 h before the solvent was removed invacuo. The residue was taken up in acetonitrile (50 mL) and hexanes (50mL) and the resulting mixture was washed twice with hexanes. Theacetonitrile layer was then separated, filtered through Celite, andevaporated. Purification of the residue by flash chromatography on aHorizon instrument (gradient elution with 25% ethyl acetate in hexanesto 65% ethyl acetate in hexanes) afforded methyl 3-vinylpicolinate (i.e.Cap-175, step a) (130 mg, 40%) as a yellow oil. ¹H NMR (300 MHz, CDCl₃)δ ppm 8.60 (1H, dd, J=4.6, 1.7 Hz), 7.94 (1H, d, J=7.7 Hz), 7.33-7.51(2H, m), 5.72 (1H, d, J=17.2 Hz), 5.47 (1H, d, J=11.0 Hz), 3.99 (3H, s).R_(t)=1.29 min (Cond.-MD1); LC/MS: Anal. Calcd. for [M+H]⁺ C₉H₁₀NO₂:164.07. found: 164.06.

Cap-175, Step B

Palladium on carbon (10%, 25 mg) was added to a solution of methyl3-vinylpicolinate (120 mg, 0.74 mmol) in ethanol (10 mL). The suspensionwas stirred at room temperature under an atmosphere of hydrogen for 1 hbefore it was filtered through Celite and the pad of Celite was washedwith methanol. The filtrate was concentrated down to dryness to yieldmethyl 3-ethylpicolinate (i.e. Cap-175, step b) which was taken directlyinto the next reaction. R_(t)=1.15 min (Cond.-MD1); LC/MS: Anal. Calcd.for [M+H]⁺ C₉H₁₂NO₂: 166.09. found: 166.09.

Cap-175

To a solution of methyl 3-ethylpicolinate in THF/H₂O/MeOH (5 mL/0.75mL/3 mL) was added LiOH (35 mg, 1.47 mmol). The mixture was stirred atroom temperature for 2 d before additional LiOH (80 mg) was added. Afteran additional 24 h at room temperature, the mixture was filtered and thesolvent was removed in vacuo. The residue was then treated with 4N HClin dioxanes (5 mL) and the resulting suspension was concentrated down todryness to yield Cap-175 as a yellow solid which was used withoutfurther purification. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.47 (1H, dd,J=4.8, 1.5 Hz), 7.82-7.89 (1H, m), 7.53 (1H, dd, J=7.7, 4.8 Hz), 2.82(2H, q, J=7.3 Hz), 1.17 (3H, t, J=7.5 Hz). R_(t)=0.36 min (Cond.-MD1);LC/MS: Anal. Calcd. for [M+H]⁺ C₈H₁₀NO₂: 152.07. found: 152.10.

Cap-176

Cap-176, Step A

A solution of 1,4-dioxaspiro[4.5]decan-8-one (15 g, 96 mmol) in EtOAc(150 mL) was added to a solution of methyl2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (21.21 g, 64.0mmol) in 1,1,3,3-tetramethylguanidine (10.45 mL, 83 mmol) and EtOAc (150mL). The resulting solution was the stirred at ambient temperature for72 h and then it was diluted with EtOAc (25 mL). The organic layer waswashed with 1N HCl (75 mL), H2O (100 mL) and brine (100 mL), dried(MgSO₄), filtered and concentrated. The residue was purified via Biotage(5% to 25% EtOAc/Hexanes; 300 g column). The combined fractionscontaining the product were then concentrated under vacuum and theresidue was re-crystallized from hexanes/EtOAc to give white crystalsthat corresponded to methyl2-(benzyloxycarbonylamino)-2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate(6.2 g) ¹H NMR (400 MHz, CDCl₃-d) δ ppm 7.30-7.44 (5H, m), 6.02 (1H, br.s.), 5.15 (2H, s), 3.97 (4H, s), 3.76 (3H, br. s.), 2.84-2.92 (2H, m),2.47 (2H, t, J=6.40 Hz), 1.74-1.83 (4H, m). LC (Cond. OL1): R_(t)=2.89min. LC/MS: Anal. Calcd. For [M+Na]⁺ C₁₉H₂₃NNaO₆: 745.21. found: 745.47

Cap 176, Step B

Ester Cap 176, step b was prepared from alkene Cap 176, step a accordingto the method of Burk, M. J.; Gross, M. F. and Martinez J. P. (J. Am.Chem. Soc., 1995, 117, 9375-9376 and references therein): A 500 mLhigh-pressure bottle was charged with alkene Cap 176, step a (3.5 g,9.68 mmol) in degassed MeOH (200 mL) under a blanket of N₂. The solutionwas then charged with(−)-1,2-Bis((2S,5S)-2,5-dimethylphospholano)ethane(cyclooctadiene)rhodium(I) tetrafluoroborate (0.108 g, 0.194 mmol) and the resulting mixturewas flushed with N₂ (3×) and charged with H₂ (3×). The solution wasshaken vigorously under 70 psi of H₂ at ambient temperature for 72 h.The solvent was removed under reduced pressure and the remaining residuewas taken up in EtOAc. The brownish solution was then filtered through aplug of Silica Gel and eluted with EtOAc. The solvent was concentratedunder vacuum to afford a clear oil corresponding to ester Cap 176, stepb (3.4 g). ¹H NMR (500 MHz, CDCl₃-d) δ ppm 7.28-7.43 (5H, m), 5.32 (1H,d, J=9.16 Hz), 5.06-5.16 (2H, m), 4.37 (1H, dd, J=9.00, 5.04 Hz), 3.92(4H, t, J=3.05 Hz), 3.75 (3H, s), 1.64-1.92 (4H, m), 1.37-1.60 (5H, m).LC (Cond. OL1): R_(t)=1.95 min. LC/MS: Anal. Calcd. For [M+H]⁺C₁₉H₂₆NO₆: 364.18. found: 364.27.

Cap 176, Step c

Ester Cap 176, step b (4.78 g, 13.15 mmol) was dissolved in THF (15 mL)followed by sequential addition of water (10 mL), glacial acetic acid(26.4 mL, 460 mmol) and dichloroacetic acid (5.44 mL, 65.8 mmol). Theresulting mixture was stirred for 72 h at ambient temperature, and thereaction was quenched by slow addition of solid Na₂CO₃ with vigorousstirring until the release of gas was no longer visible. Crude productwas extracted into 10% ethyl acetate-dichloromethane and the organiclayers were combined, dried (MgSO₄) filtered and concentrated. Theresulting residue was purified via Biotage (0 to 30% EtOAc/Hex; 25 gcolumn) to afford ketone Cap 176, step c (3.86 g) as a clear oil. ¹H NMR(400 MHz, CDCl₃-d) δ ppm 7.28-7.41 (5H, m), 5.55 (1H, d, J=8.28 Hz),5.09 (2H, s), 4.46 (1H, dd, J=8.16, 5.14 Hz), 3.74 (3H, s), 2.18-2.46(5H, m), 1.96-2.06 (1H, m), 1.90 (1H, ddd, J=12.99, 5.96, 2.89 Hz),1.44-1.68 (2H, m, J=12.36, 12.36, 12.36, 12.36, 4.77 Hz). LC (Cond.OL1): R_(t)=1.66 min. LC/MS: Anal. Calcd. For [M+Na]⁺ C₁₇H₂₁NNaO₅:342.13. found: 342.10.

Cap 176, Step d

Deoxo-Fluor® (3.13 mL, 16.97 mmol) was added to a solution of ketone Cap176, step c (2.71 g, 8.49 mmol) in CH₂Cl₂ (50 mL) followed by additionof a catalytic amount of EtOH (0.149 mL, 2.55 mmol). The resultingyellowish solution was stirred at rt overnight. The reaction wasquenched by addition of sat. aq. NaHCO₃ (25 mL) and the mixture wasextracted with EtOAc (3×75 mL)). The combined organic layers were dried(MgSO₄), filtered and dried to give a yellowish oil. The residue waspurified via Biotage chromatography (2% to 15% EtOAc/Hex; 90 g column)and a white solid corresponding to the difluoro amino acid dilforide Cap176, step d (1.5 g) was recovered. ¹H NMR (400 MHz, CDCl₃-d) δ ppm7.29-7.46 (5H, m), 5.34 (1H, d, J=8.28 Hz), 5.12 (2H, s), 4.41 (1H, dd,J=8.66, 4.89 Hz), 3.77 (3H, s), 2.06-2.20 (2H, m), 1.83-1.98 (1H, m),1.60-1.81 (4H, m), 1.38-1.55 (2H, m). ¹⁹F NMR (376 MHz, CDCl₃-d) δ ppm−92.15 (1F, d, J=237.55 Hz), −102.44 (1F, d, J=235.82 Hz). LC (Cond.OL1): R_(t)=1.66 min. LC/MS: Anal. Calcd. For [2M+Na]⁺ C₃₄H₄₂F₄N₂NaO₈:705.28. found: 705.18.

Cap 176, Step e

Difluoride Cap 176, step d (4 g, 11.72 mmol) was dissolved in MeOH (120mL) and charged with Pd/C (1.247 g, 1.172 mmol). The suspension wasflushed with N₂ (3×) and the reaction mixture was placed under 1 atm ofH₂ (balloon). The mixture was stirred at ambient temperature for 48 h.The suspension was then filtered though a plug of Celite andconcentrated under vacuum to give an oil that corresponded to amino acidCap 176, step e (2.04 g) and that was used without further purification.¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.62 (3H, s), 3.20 (1H, d, J=5.77 Hz),1.91-2.09 (2H, m), 1.50-1.88 (7H, m), 1.20-1.45 (2H, m). ¹⁹F NMR (376MHz, DMSO-d₆) δ ppm −89.39 (1F, d, J=232.35 Hz), −100.07 (1F, d,J=232.35 Hz). ¹³C NMR (101 MHz, DMSO-d₆) δ ppm 175.51 (1C, s), 124.10(1C, t, J=241.21, 238.90 Hz), 57.74 (1C, s), 51.39 (1C, s), 39.23 (1C,br. s.), 32.02-33.83 (2C, m), 25.36 (1C, d, J=10.02 Hz), 23.74 (1C, d,J=9.25 Hz). LC (Cond. OL2): R_(t)=0.95 min. LC/MS: Anal. Calcd. For[2M+H]⁺ C₁H₃₁F₄N₂O₂: 415.22. found: 415.40.

Cap 176, Step f

Methyl chloroformate (1.495 mL, 19.30 mmol) was added to a solution ofamino acid Cap 176, step e (2 g, 9.65 mmol) and DIEA (6.74 mL, 38.6mmol) in CH₂Cl₂ (100 mL). The resulting solution was stirred at rt for 3h and volatiles were removed under reduced pressure. The residue waspurified via Biotage (0% to 20% EtOAc/Hex; 90 g column). A clear oilthat solidified upon standing under vacuum and corresponding tocarbamate Cap-176, step f (2.22 g) was recovered. ¹H NMR (500 MHz,CDCl₃-d) δ ppm 5.27 (1H, d, J=8.55 Hz), 4.39 (1H, dd, J=8.85, 4.88 Hz),3.77 (3H, s), 3.70 (3H, s), 2.07-2.20 (2H, m), 1.84-1.96 (1H, m),1.64-1.82 (4H, m), 1.39-1.51 (2H, m). ¹⁹F NMR (471 MHz, CDCl₃-d) δ ppm−92.55 (1F, d, J=237.13 Hz), −102.93 (1F, d, J=237.12 Hz). ¹³C NMR (126MHz, CDCl₃-d) δ ppm 171.97 (1C, s), 156.69 (1C, s), 119.77-125.59 (1C,m), 57.24 (1C, br. s.), 52.48 (1C, br. s.), 52.43 (1C, s), 39.15 (1C,s), 32.50-33.48 (2C, m), 25.30 (1C, d, J=9.60 Hz), 24.03 (1C, d, J=9.60Hz). LC (Cond. OL1): R_(t)=1.49 min. LC/MS: Anal. Calcd. For [M+Na]⁺C₁₁H₁₇F₂NNaO₄: 288.10. found: 288.03.

Cap-176

A solution of LiOH (0.379 g, 15.83 mmol) in Water (25 mL) was added to asolution of carbamate Cap-176, step f (2.1 g, 7.92 mmol) in THF (75 mL)and the resulting mixture was stirred at ambient temperature for 4 h.THF was removed under vacuum and the remaining aqueous phase wasacidified with 1N HCl solution (2 mL) and then extracted with EtOAc(2×50 mL). The combined organic layers were dried (MgSO₄), filtered andconcentrated to give a white foam corresponding to Cap-176 (1.92 g). ¹HNMR (400 MHz, DMSO-d₆) δ ppm 12.73 (1H, s), 7.50 (1H, d, J=8.78 Hz),3.97 (1H, dd, J=8.53, 6.02 Hz), 3.54 (3H, s), 1.92-2.08 (2H, m),1.57-1.90 (5H, m), 1.34-1.48 (1H, m), 1.27 (1H, qd, J=12.72, 3.26 Hz).¹⁹F NMR (376 MHz, DMSO-d₆) δ ppm −89.62 (1F, d, J=232.35 Hz), −99.93(1F, d, J=232.35 Hz). LC (Cond. OL2): R_(t)=0.76 min. LC/MS: Anal.Calcd. For [M−H] C₁₀H₁₄F₂NO₄. 250.09. found: 250.10.

EXAMPLES

The present disclosure will now be described in connection with certainembodiments which are not intended to limit its scope. On the contrary,the present disclosure covers all alternatives, modifications, andequivalents as can be included within the scope of the claims. Thus, thefollowing examples, which include specific embodiments, will illustrateone practice of the present disclosure, it being understood that theexamples are for the purposes of illustration of certain embodiments andare presented to provide what is believed to be the most useful andreadily understood description of its procedures and conceptual aspects.

Solution percentages express a weight to volume relationship, andsolution ratios express a volume to volume relationship, unless statedotherwise. Nuclear magnetic resonance (NMR) spectra were recorded eitheron a Bruker 300, 400, or 500 MHz spectrometer; the chemical shifts (δ)are reported in parts per million.

Purity assessment and low resolution mass analysis were conducted on aShimadzu LC system coupled with Waters Micromass ZQ MS system. It shouldbe noted that retention times may vary slightly between machines. Unlessnoted otherwise, the LC conditions employed in determining the retentiontime (R_(t)) were:

Cond.-J1 Column=Phenomenex-Luna 3.0×50 mm S10 Start % B=0 Final % B=100

Gradient time=2 minStop time=3 minFlow Rate=4 mL/min

Wavelength=220 nm

Slovent A=0.1% TFA in 10% methanol/90% waterSolvent B=0.1% TFA in 90% methanol/10% water

Cond.-J2 Column=Phenomenex-Luna 3.0×50 mm S10 Start % B=0 Final % B=100

Gradient time=4 minStop time=5 minFlow Rate=4 mL/min

Wavelength=220 nm

Slovent A=0.1% TFA in 10% methanol/90% waterSolvent B=0.1% TFA in 90% methanol/10% water

Cond.-J3 Column=XTERRA C18 S7 (3.0×50 mm) Start % B=0 Final % B=100

Gradient time=2 minStop time=3 minFlow Rate=5 mL/min

Wavelength=220 nm

Solvent A=0.1% TFA in 10% methanol/90% waterSolvent B=0.1% TFA in 90% methanol/10% water

Cond.-D1 Column=Phenomenex-Luna 3.0×50 mm S10 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Slovent A=0.1% TFA in 10% methanol/90% waterSolvent B=0.1% TFA in 90% methanol/10% water

Cond.-D2 Column=Phenomenex-Luna 4.6×50 mm S10 Start % B=0 Final % B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Slovent A=0.1% TFA in 10% methanol/90% waterSolvent B=0.1% TFA in 90% methanol/10% water

Cond.-JR-1 Column=Waters Sunfire 5u C18 4.6×30 mm Start % B=0 Final %B=100

Gradient time=3 minStop time=4 minFlow Rate=4 mL/min

Wavelength=220 nm

Slovent A=0.1% TFA in 10% acetonitrile/90% waterSolvent B=0.1% TFA in 90% acetonitrile/10% water

Examples J.1-J.5

A 1M solution of potassium tert-butoxide in tetrahydrofuran (80 mL) wasadded dropwise to (3-carboxypropyl)triphenylphosphonium bromide (17 g,40 mol) in anhydrous DMSO (20 mL) under nitrogen at 24° C., and thesolution was stirred 30 min. before addition of 3-bromobenzaldehyde (4.7mL, 40 mmol). After several minutes a precipitate was observed and anadditional 20 mL of DMSO was added to aid solvation, and the reactionwas stirred 18 h. The solution was poured onto water (120 mL) and washedwith chloroform. The aqueous layer was acidified with conc. HCl andextracted with chloroform (3×250 mL). The organic phase was concentratedand applied to a 65i Biotage silica gel column, gradient elution from15-65% B (A=Hexanes; B=ethyl acetate) over 2 L to give J.1,(E)-5-(3-bromophenyl)pent-4-enoic acid, 8.2 g (82%). ¹H NMR (300 MHz,CDCl₃) δ 7.45 (t, J=1.5 Hz, 1H), 7.30 (dt, J=7.7, 1.5 Hz, 1H), 7.2-7.16(m, 1H), 7.12 (t, J=7.7 Hz, 1H), 6.40-6.32 (m, 1H), 6.23-6.14 (m, 1H),2.52 (s, 4H). LC (Cond.-J1): RT=2.0 min; LRMS: Anal. Calcd. for [M−H]⁻C₁₁H₁₁BrO₂: 252.97. found: 252.98.

J.1, (E)-5-(3-Bromophenyl)pent-4-enoic acid (4 g, 15.8 mmol) wasdissolved in absolute ethanol (200 mL) and flushed with nitrogen beforeaddition of 5% platinum sulfide on carbon (2.5 g). The solution wasflushed with hydrogen at atmospheric pressure and stirred 5 h. Thecatalyst was removed by filtration over diatomaceous earth (Celite®) andthe solvent immediately removed by rotory evaporation (in order tominimized esterification) to give J.2, 5-(3-bromophenyl)pentanoic acid 4g (99%) which was carried forward without further purification. ¹H NMR(500 MHz, CDCl₃) δ 7.31-7.30 (m, 2H), 7.13 (t, J=7.6 Hz, 1H), 7.09-7.07(d, J=7.6 Hz, 1H), 2.60 (t, J=7.0 Hz, 2H), 2.37 (t, J=7.0 Hz, 2H),1.68-1.65 (m, 4H). LC (Cond.-J1): RT=2.1 min; LRMS: Anal. Calcd. for[M−H]⁻ C₁₁H₁₃BrO₂: 255.00. found: 254.99.

J.2, 5-(3-bromophenyl)pentanoic acid (4 g, 15.6 mmol) was taken up inpolyphosphoric acid (15 g) and heated to 140° C. for 8 h in a 150 mLpressure vessel, capped to prevent product loss due to sublimation. Thereaction mixture was partitioned between 150 mL of water anddichloromethane (600 mL). [Caution is necessary to avoid boiling ofdichloromethane.] The organic phase was washed with water, brine, andconcentrated. The crude product was applied to a 40 (S) Biotage silicagel column and gradient eluted from 5-60% (ethyl acetate/hexanes) andgave J.3 2-bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 1.7 g(40%). ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J=8.1 Hz, 1H), 7.41 (dd, J=8.4Hz, 1.8 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H), 2.86 (t, J=5.9 Hz, 2H), 2.69(t, J=5.8 Hz, 2H), 1.90-1.73 (m, 4H). LC (Cond.-J1): RT=2.1 min; LRMS:Anal. Calcd. for [M+H]⁺ C₁₁H₁₁BrO: 239.00. found: 239.14.

J.3, 2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.5 g, 5.9mmol) was dissolved in 2:1 ether/tetrahydrofuran (120 mL) and 1N HCl inether (9 mL) was added. The solution was cooled to 0° C. before additionof isoamyl nitrite (1.2 mL, 9 mmol) and the reaction was stirred 18 h at24° C., concentrated, and applied to 25 (M) Biotage silica gel column.Gradient elution from 15-100% B (A=Hexanes; B=ethyl acetate) over 1 Land gave J.3a(E)-2-bromo-6-(hydroxyimino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one1 g (64%). LC (Cond.-J1); RT=1.9 min; LC/MS: Anal. Calcd. for [M+H]⁺C₁₁H₁₀NBrO₂: 268. found: 268.

Concentrated ammonium hydroxide (12 mL, 28%) was added to a solution ofJ.3a(E)-2-bromo-6-(hydroxyimino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one(1 g, 3.7 mmol) and N-Boc-L-prolinal (850 mg, 4.3 mmol) in methanol (35mL) and the reaction stirred 18 h at 24° C. The reaction mixture wasconcentrated to remove methanol, the aqueous solution extracted withdichloromethane, and the organic phase washed with water. Application ofthe crude product in dichloromethane to a 40 (S) Biotage silica gelcolumn and subjection to gradient elution; Segment 1.15%-30% B over 300mL; Segment 2.30%-100% B over 700 mL (A=1:1 hexanes/dichloromethane;B=ethyl acetate) gave J.4 700 mg (44%). ¹H NMR (300 MHz, DMSO-d₆) δ 11.3(br. s, 1H), 7.91 (d, J=8.4 Hz, 1H), 7.35 (dd, J=8.4, 1.5 Hz, 1H), 7.31(d, J=1.8 Hz, 1H), 5.0/4.87 (m, 1H), 3.51-3.46 (m, 1H), 3.42-3.36 (m,1H), 2.90-2.70 (m, 4H), 2.27-1.80 (m, 6H), 1.38/1.11 (s, 9H). LC(Cond.-J1): RT=1.9 min; LRMS: Anal. Calcd. For [M+H]⁺ C₂₁H₂₆BrN₃O₃:488.12. found: 488.14. HRMS: Anal. Calcd. for [M+H]⁺ C₂₁H₂₆BrN₃O₃:488.1236. found: 488.1242.

Triethyl phosphite (0.78 mL, 4.7 mmol) was added to a solution of J.4(700 mg, 1.57 mmol) in dimethylformamide (2 mL) and the solution heatedat 80° C. for 18 h under a nitrogen atmosphere. The reaction mixture wastaken up in ethyl acetate (100 mL) and washed with water and brine.After concentration the crude product was applied to a 40 (S) Biotagesilica gel column and subjected to gradient elution; Segment 1.5%-15% Bover 300 mL; Segment 2.15%-100% B over 600 mL (A=dichloromethane;B=ethyl acetate) to give J.5 675 mg (100%). ¹H NMR (300 MHz, DMSO-d₆) δ11.7 (br. s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.29(s, 1H), 4.78/4.69 (br s, 1H), 3.57-3.48 (m, 1H), 3.38-3.32 (m, 1H),2.85-2.78 (m, 4H), 2.28-1.77 (m, 6H), 1.39/1.14 (s, 9H). LC (Cond.-J1):RT=1.9 min; LRMS: Anal. Calcd. for [M+H]⁺ C₂₁H₂₆BrN₃O₂: 432.13. found:432.14.

Examples M.1-M.4

To a solution of (S)-5-(hydroxymethyl)pyrrolidin-2-one (10 g, 87 mmol)in dichloromethane (50 mL) was added tert-butylchlorodiphenylsilane(25.6 g, 93 mmol), Et₃N (12.1 mL, 87 mmol) and DMAP (1.06 g, 8.7 mmol).The mixture was stirred at room temperature until the startingpyrrolidinone was completely consumed, and then it was diluted withdichloromethane (50 mL) and washed with water (50 mL). The organic layerwas dried (Na₂SO₄), filtered, and concentrated in vacuo, and the crudematerial was submitted to flash chromatography (silica gel; 30 to 100%of ethyl acetate/hexanes) to afford the silyl ether as a colorless oil(22.7 g, 74% yield). ¹H-NMR (400 MHz, DMSO-d₆, δ=2.5 ppm) 7.69 (br s,1H), 7.64-7.61 (m, 4H), 7.50-7.42 (m, 6H), 3.67-3.62 (m, 1H), 3.58-3.51(m, 2H), 2.24-2.04 (m, 3H), 1.87-1.81 (m, 1H), 1.00 (s, 9H). LC/MS[M+H]⁺=354.58.

Di-tert-butyl dicarbonate (38.5 g, 177 mmol) was added in portions as asolid over 10 min to a dichloromethane (200 mL) solution of silyl ether(31.2 g, 88.3 mmol), Et₃N (8.93 g, 88 mmol), and DMAP (1.08 g, 8.83mmol) and stirred for 18 h at 24° C. Most of the volatile material wasremoved in vacuo and the crude material taken up in 20% ethylacetate/hexanes and applied to a 2 L funnel containing 1.3 L of silicagel and then eluted with 3 L of 20% ethyl acetate/hexane and 2 L of 50%ethyl acetate). Upon concentration of the desired fractions in a rotaryevaporator, a white slurry of solid formed which was filtered, washedwith hexaness and dried in vacuo to afford carbamate M.1 as a whitesolid (32.65 g, 82% yield). ¹H NMR (400 MHz, DMSO-d₆, δ=2.5 ppm)7.61-7.59 (m, 2H), 7.56-7.54 (m, 2H), 7.50-7.38 (m, 6H), 4.18 (m, 1H),3.90 (dd, J=10.4, 3.6, 1H), 3.68 (dd, J=10.4, 2.1, 1H), 2.68-2.58 (m,1H), 2.40-2.33 (m, 1H), 2.22-2.12 (m, 1H), 2.01-1.96 (m, 1H), 1.35 (s,9H), 0.97 (s, 9H). LC/MS [M-Boc+H]⁺=354.58. Calcd. 454.24.

A three-necked flask equipped with a thermometer and a nitrogen inletwas charged with carbamate M.1 (10.05 g, 22.16 mmol) and toluene (36mL), and lowered into −55° C. cooling bath. When the internaltemperature of the mixture reached −50° C., lithium triethylborohydride(23 mL of 1.0 M/tetrahydrofuran, 23.00 mmol) was added dropwise over 30min and the mixture stirred for 35 min while maintaining the internaltemperature between −50° C. and −45° C. Hunig's base (16.5 mL, 94 mmol)was added dropwise over 10 min. Then, DMAP (34 mg, 0.278 mmol) was addedin one batch, followed by the addition of trifluoroacetic anhydride (3.6mL, 25.5 mmol) over 15 min, while maintaining the internal temperaturebetween −50° C. and −45° C. The bath was removed 10 min later, and thereaction mixture was stirred for 14 h while allowing it to rise toambient temperature. It was diluted with toluene (15 mL), cooled with anice-water bath, and treated slowly with water (55 mL) over 5 min. Thephases were separated and the organic layer washed with water (50 mL,2×) and concentrated in vacuo. The crude material was purified by flashchromatography (silica gel; 5% ethyl acetate/hexanes) to afforddihydropyrrole M.2 as a colorless viscous oil (7.947 g, 82% yield).Rt=2.41 min under the following HPLC conditions: Solvent gradient from100% A: 0% B to 0% A: 100% B (A=0.1% TFA in 1:9 methanol/water; B=0.1%TFA in 9:1 methanol/water) over 2 min and hold for 1 min; detection @220 nm; Phenomenex-Luna 3.0×50 mm S10 column. ¹H-NMR (400 MHz, DMSO-d₆,δ=2.5 ppm) 7.62-7.58 (m, 4H), 7.49-7.40 (m, 6H), 6.47 (br s, 1H),5.07/5.01 (overlapping br d, 1H), 4.18 (br s, 1H), 3.89 (br s, 0.49H),3.69 (br s, 1.51H), 2.90-2.58 (br m, 2H), 1.40/1.26 (overlapping br s,9H), 0.98 (s, 9H). LC/MS: [M+Na]⁺=460.19.

Diethylzinc (19 mL of ˜1.1 M in toluene, 20.9 mmol) was added dropwiseover 15 min to a cooled (−30° C.) toluene (27 mL) solution ofdihydropyrrole M.2 (3.94 g, 9.0 mmol). Chloroiodomethane (stabilizedover copper; 3.0 mL, 41.2 mmol) was added dropwise over 10 min, andstirred while maintaining the bath temperature at −25° C. for 1 h andbetween −25° C. and −21° C. for 18.5 h. The reaction mixture was openedto the air and quenched by the slow addition of 50% saturated NaHCO₃solution (40 mL), and then removed from the cooling bath and stirred atambient temperature for 20 min. It was filtered through a filter paperand the white cake was washed with 50 mL of toluene. The organic phaseof the filtrate was separated and washed with water (40 mL, 2×), dried(MgSO₄), filtered, and concentrated in vacuo. The crude material waspurified using a Biotage system (350 g silica gel; sample was loadedwith 7% ethyl acetate/hexanes; eluted with 7-20% ethyl acetate/hexanes)to afford a mixture of methanopyrrolidines (M.3 predominates) as acolorless viscous oil (3.69 g, 90.7%). [Note: the exact cis/trans-isomerratio was not determined at this stage]. Rt=2.39 min under the followingHPLC conditions: Solvent gradient from 100% A: 0% B to 0% A: 100% B(A=0.1% TFA in 1:9 methanol/water; B=0.1% TFA in 9:1 methanol/water)over 2 min, and hold for 1 min; detection @ 220 nm; Phenomenex-Luna3.0×50 mm S10 column. ¹H-NMR (400 MHz, DMSO-d₆, δ=2.5 ppm) 7.62-7.60 (m,4H), 7.49-7.40 (m, 6H), 3.77/3.67 (overlapping br s, 3H), 3.11-3.07 (m,1H), 2.23 (app br s, 1H), 2.05-2.00 (m, 1H), 1.56-1.50 (m, 1H), 1.33(very broad s, 9H), 1.00 (s, 9H), 0.80 (m, 1H), 0.30 (m, 1H). LC/MS:[M+Na]⁺=474.14.

TBAF (7.27 mL of 1.0 M in tetrahydrofuran, 7.27 mmol) was added dropwiseover 5 min to a tetrahydrofuran (30 mL) solution of silyl ethers M.3(3.13 g, 6.93 mmol) and the mixture stirred at ambient temperature for4.75 h. After the addition of saturated ammonium chloride solution (5mL), most of the volatile material was removed in vacuo and the residuepartitioned between dichloromethane (70 mL) and 50% saturated ammoniumchloride solution (30 mL). The aqueous phase was extracted withdichloromethane (30 mL), and the combined organic phase was dried(MgSO₄), filtered, concentrated in vacuo and then exposed to high vacuumovernight. The crude material was purified using a Biotage (silica gel;40-50% ethyl acetate/hexanes) to afford a mixture of alcohols,contaminated with traces of a lower Rf spot, as a colorless oil (1.39 g,˜94% yield). [Note: the exact cis/trans isomer ratio was not determinedat this stage.] ¹H-NMR (400 MHz, dimethylsulfoxide-d₆, δ=2.5 ppm) 4.70(t, J=5.7, 1H), 3.62-3.56 (m, 1H), 3.49-3.44 (m, 1H), 3.33-3.27 (m, 1H),3.08-3.04 (m, 1H), 2.07 (br m, 1H), 1.93-1.87 (m, 1H), 1.51-1.44 (m,1H), 1.40 (s, 9H), 0.76-0.71 (m, 1H), 0.26 (m, 1H). LC/MS[M+Na]⁺=236.20.

A semi-solution of sodium periodate (6.46 g, 30.2 mmol) in water (31 mL)was added to a solution of alcohols (2.15 g, 10.08 mmol) in acetonitrile(20 mL) and carbon tetrachloride (20 mL). Ruthenium trichloride (0.044g, 0.212 mmol) was added immediately and the heterogeneous reactionmixture was stirred vigorously for 75 min. The reaction mixture wasdiluted with water (60 mL) and extracted with dichloromethane (50 mL,3×). The combined organic phase was treated with 1 mL methanol, allowedto stand for about 5 min, and then filtered through diatomaceous earth.The pad was washed with dichloromethane (50 mL), and the filtrate wasconcentrated in vacuo to afford a light charcoal-colored solid. Thecrude material was dissolved in ethyl acetate (˜10 mL) with heating andallowed to stand at ambient temperature with seeding. About 15 min intothe cooling phase, a rapid crystal formation was observed. About 1 hlater, hexanes (˜6 mL) was added and the mixture refrigerated overnight(it did not appear that additional material precipitated out). Themixture was filtered and washed with ice/water-cooled hexanes/ethylacetate (2:1 ratio; 20 mL) and dried under high vacuum to afford thefirst crop of acid M.4 (off-white crystals, 1.222 g). The mother liquorwas concentrated in vacuo, and the residue dissolved in ˜3 mL of ethylacetate with heating, allowed to stand at ambient temperature for 1 h,and then 3 mL hexanes was added and stored in a refrigerator for ˜15 h.A second crop of acid M.4 was retrieved similarly (grey crystals, 0.133g), for a combined yield of 59%. Rt=1.48 min under the following HPLCconditions: Solvent gradient from 100% A: 0% B to 0% A: 100% B (A=0.1%TFA in 1:9 methanol/water; B=0.1% TFA in 9:1 methanol/water) over 3 min;detection @ 220 nm; Phenomenex-Luna 3.0×50 mm S10 column. MP (dec.) forthe first crop=147.5-149.5° C. ¹H-NMR (400 MHz, DMSO-d₆, δ=2.5 ppm)12.46 (s, 1H), 3.88 (app br s, 1H), 3.27 (app br s, 1H; overlapped withwater signal), 2.28 (br m, 1H), 2.07 (app br s, 1H), 1.56 (app s, 1H),1.40/1.34 (two overlapped s, 9H), 0.71 (m, 1H), 0.45 (m, 1H). ¹³C-NMR(100.6 MHz, DMSO-d₆, δ=39.21 ppm) 172.96, 172.60, 154.45, 153.68, 78.74,59.88, 59.58, 36.91, 31.97, 31.17, 27.77, 27.52, 14.86, 14.53, 13.69.LC/MS [M+Na]⁺=250.22. Anal. Calcd. For C11HNO4: C, 58.13; H, 7.54; N,6.16. Found (for first crop): C, 58.24; H, 7.84; N, 6.07. Opticalrotation (10 mg/mL in CHCl₃): [α]_(D)=−216 and −212 for the first andsecond crop, respectively.

ExampleM.4a

The synthesis of acid M.4a is reported in patent application:US2009/0068140.

Examples J.6-J.7b

N,N-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g,33.17 mmol), HATU (13.324 g, 35.04 mmol), the HCl salt of2-amino-1-(4-bromo-phenyl)ethanone (8.127 g, 32.44 mmol), indimethylformamide (105 mL) and stirred at ambient condition for 55minutes. Dimethylformamide was removed in vacuo, and the resultingresidue was partitioned between ethyl acetate (300 mL) and water (200mL). The organic layer was washed with water (200 mL) and brine, dried(MgSO₄), filtered, and concentrated. A silica gel mesh was prepared fromthe residue and submitted to flash chromatography (silica gel; 50-60%ethyl acetate/hexanes) to provide J.6 (S)-tert-butyl2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)pyrrolidine-1-carboxylate as awhite solid (12.8 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ 8.25-8.14(m, 1H), 7.92 (br d, J=8.0, 2H), 7.75 (br d, J=8.6, 2H), 4.61 (dd,J=18.3, 5.7, 1H), 4.53 (dd, J=18.1, 5.6, 1H), 4.22-4.12 (m, 1H),3.43-3.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m,3H), 1.40/1.34 (two app br s, 9H). LC (Cond.-J1): RT=1.70 min; LCMS:Anal. Calcd. For [M+Na]⁺ C₁₈H₂₃BrN₂NaO₄: 433.07. found 433.09.

J.6a

LRMS: Anal. Calcd. For [M + Na]⁺ C₁₈H₂₃BrN₂NaO₄: 433.07; found: 433.12J.6b

  From M.4 LC (Cond.-J1): RT = 1.7 min; Anal. Calcd. For [M + Na]⁺C₁₉H₂₃BrN₂NaO₄: 445.08; found: 446.93.

A mixture J.6 (S)-tert-butyl2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-pyrrolidine-1-carboxylate(12.8 g, 31.12 mmol) and ammonium acetate (12.0 g, 155.7 mmol) inxylenes (155 mL) was heated in a sealed tube at 140° C. for 2 hours. Thevolatile component was removed in vacuo, and the residue was partitionedcarefully between ethyl acetate and water, whereby enough saturatedNaHCO₃ solution was added so as to make the pH of the aqueous phaseslightly basic after the shaking of the biphasic system. The layers wereseparated, and the aqueous layer was extracted with an additional ethylacetate. The combined organic phase was washed with brine, dried(MgSO₄), filtered, and concentrated. The resulting material wasrecrystallized from ethyl acetate/hexanes to provide two crops of J.7(S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate, 5.85 g.The mother liquor was concentrated in vacuo and submitted to a flashchromatography (silica gel; 30% ethyl acetate/hexanes) to provide anadditional 2.23 g. ¹H NMR (DMSO-d₆, δ=2.5 ppm, 400 MHz): δ12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H),3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app brs, 9H). LC (Cond.-J1): RT=1.71 min; LC/MS: Anal. Calcd. For [M+H]⁺C₁₈H₂₃BrN₃O₂: 392.10. found 391.96. HRMS: Anal. Calcd. For [M+H]⁺C₁₈H₂₃BrN₃O₂: 392.0974. found 392.0959.

J.7a

  From J.6a LRMS: Anal. Calcd. For [M + H]⁺ C₁₈H₂₃BrN₃O₂: 392.10; found:391.96. J.7b

  From J.6b LC (Cond.- J1): RT = 1.5 min; Anal. Calcd. For [M + H]⁺C₁₉H₂₃BrN₃O₂: 405.09; found: 406.04.

Examples J.8-J.9e

Bromine (0.23 mL, 4.18 mmol) was added dropwise to a solution of J.32-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (1.0 g, 4.18 mmol)in ether (50 mL), after being cooled to 0° C. The solution was stirred 3h and a few drops of additional bromine was and while the reaction wasfollowed by TLC until complete. The solvent was removed by rotoryevaporation, the residue was taken up in acetonitrile (25 mL), M.4 (950mg, 4.18 mmol), and Hunig's base (1.4 mL) added dropwise. The reactionwas stirred 18 hours at 60° C. prior to removal of the solvent by rotoryevaporation. The crude product charged (dichloromethane) to a 40 gThompson silica gel cartridge and gradient elution 15-100% B over 1 L(A/B hexanes/ethyl acetate) gave J.8(1R,3S,5R)-3-(2-bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)2-tert-butyl 2-azabicyclo[3.1.0]hexane-2,3-dicarboxylate 1 g (51.5%) asan oil. RT=2.2 minutes (Cond.-J1). LCMS: Anal. Calcd. for C₂₂H₂₆BrNO₅Na:486.10. found: 486.07 (M+Na)⁺.

J.8a (Derived from 6-bromo tetral- 1-one purchased from J & W PharmLab,LLC)

RT = 3.1 min (Cond.- D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₀H₂₅BrNO₅:438; found: 438. J.8b (Derived from 6-bromo tetral- 1-one purchased fromJ & W PharmLab, LLC)

  From M-4 RT = 2.99 min (Cond. D2), LCMS: Calcd for C₂₁H₂₅BrNO₅ [M +Na]⁺ 472.07; found: 472.10 J.8c (Derived from 4-bromo 2-fluoroacetophenone)

  From M-4 RT = 2.87 min (Cond. D2), LCMS: Calcd for C₂₉H₂₂BrFNO₅ [M +H]⁺ 464.05; found: 463.98

Ammonium acetate (1.7 g, 21.54 mmol) was added to a solution of J.8 (1.0g, 2.15 mmol) in xylene (15 mL) and the reaction mixture stirred at 140°C. for 3 h in a screw-cap pressure vessel. After being cooled, thereaction mixture was partitioned between ethyl acetate and sat'd NaHCO₃soln, and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with brine, concentrated, and theresidue applied to 20 g Thomson silica gel column. Gradient elution(10-50% B over 1 L; A/B hexanes/ethyl acetate). The major and less polarproduct (oxazole 450 mg) was separated away to afford J.9 192 mg (20%)as a diastereomeric mixture (favoring J.9; a 3:1 mixture of S/Rproline). ¹H NMR (300 MHz, CDCl₃) δ 10.6/10.3 (br. s, 1H), 8.06 (d,J=8.2 Hz, 0.6H), 7.34 (dd, J=6.4, 1.8 Hz, 1H), 7.28 (s, 0.3H), 7.21 (d,J=1.8 Hz, 0.7H), 7.11 (d, J=8.6 Hz, 0.3H), 4.83-4.77 (m, 1H), 3.48 (m,0.68H), 3.23 (m, 1.2H), 2.98 (t, J=6.4 Hz, 0.65H), 2.88 (t, H=6.7 Hz,1.35H), 2.82-2.79 (m, 2H), 2.33 (t, J=9.1 Hz, 1H), 2.01-1.95 (m, 2.4H),1.76-1.72 (m, 1H), 1.57/1. 48 (s, 9H), 0.87-0.83 (m, 1.3H), 0.44 (br. s,1H). LC (Cond.-J1): RT=1.7 min; LCMS: Anal. Calcd. for [M+H]⁺C₂₂H₂₆BrN₃O₂: 444.13. found: 444.07.

J.9a

RT = 2.4 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₀H₂₅BrN₃O₂:418.11; found: 418.10. J.9b

RT = 2.3 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₁H₂₅BrN₃O₂:430.11; found: 430.16. HRMS: Anal. Calcd. for [M + H]⁺ C₂₁H₂₅BrN₃O₂:430.1125; found 430.1123. J.9c

RT = 2.2 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₁₉H₂₂BrFN₃O₂:422.09; found: 422.10. HRMS: Anal. Calcd. for [M + H]⁺ C₁₉H₂₂BrFN₃O₂:422.0877; found 422.0874. J.9d

RT = 1.69 min, (Cond.-J1); Calcd for C₂₀H₂₇BrN₃O₂ [M + H]⁺ 420.13;found: 420.13. J.9e Obtained as the more polar product of a ~1:1 mixturecontaining the CF₃ analog.

RT = 1.55 min, (Cond.-J1); Calcd for C₂₀H₂₄BrN₄O₂ [M + H]⁺ 431.11;found: 431.15.

Example J.9f

A cold (0° C.) solution of HCl (0.871 mL, 3.49 mmol, 4N in dioxanes) wasadded to a solution of J.9b (1.5 g, 3.49 mmol) in MeOH (20 mL). Themixture was stirred for 2 h before it was concentrated to dryness. Thetan solid was taken up in dioxane (20 mL) and water (20 mL), cooled to0° C., and treated with sodium carbonate (0.369 g, 3.49 mmol) and CBZ-Cl(0.498 mL, 3.49 mmol). The reaction mixture was allowed to warm up toroom temperature, stirred for 5 h, diluted with ethyl acetate, andwashed with saturated sodium bicarbonate solution. The organic phase waswashed with brine and dried over sodium sulfate to yield J.9f (0.97 g,60%) as a tan foam, RT=2.47 min (Cond.-D1); LC/MS: Anal. Calcd. for[M+H]⁺ C₂₄H₂₃BrN₃O₂: 464.10 and 466.10. found: 463.95 and 465.98.

Examples J.9g1-J.9g

Diphenylphosphoryl azide (17.09 mL, 79 mmol) was added to a solution of6-bromo-2-naphthoic acid (16.5 g, 65.7 mmol), triethylamine (18.32 mL,131 mmol), and tert-butylalcohol (7.54 mL, 79 mmol) in toluene (225 mL)and stirred for 4 h at 100° C. The volatiles were removed by rotaryevaporation and the residue taken up in EtOAc (500 mL) and washed withwater and brine. A precipitate formed upon concentration which wasisolated by filtration and washed with 1:1 Et₂O/Hex to give ExampleJ.9g1 (10.5 g). A second crop of less pure product was isolated uponconcentration of the mother liquor (9.8 g); combined yield (93%). LC/MS(Cond. J2): RT=3.44 min. LC/MS Anal. Calcd. for [M+Na]⁺ C₁₅H₁₆BrNO₂:345.02. found 345.03.

Example J.9g1 (5 g, 15.52 mmol) was diluted in acetic acid (50 mL) andfuming nitric acid (2.3 mL) was added dropwise over 20 min. The reactionwas stirred for 2 h and the product, isolated by filtration, waspartitioned between CH₂Cl₂ and sat'd NaHCO₃ soln. The organic layer wasconcentrated to provide tert-butyl6-bromo-1-nitronaphthalen-2-ylcarbamate 5.7 g (quant). LC/MS (Cond. J2):RT=3.52 min. LC/MS Anal. Calcd. for [M+Na]⁺ C₁₅H₁₅BrN₂O₄: 390.02. found390.99.

Tin(II)chloride dehydrate (3 g, 16.34 mmol) was added to a solution oftert-butyl 6-bromo-1-nitronaphthalen-2-ylcarbamate (2 g, 5.47 mmol) inMeOH (100 mL) and the solution was stirred for 18 h at 70° C. Thesolvent was removed by rotary evaporation and Example J.9g2 (assumetheoretical 1.25 g) was dried under high vacuum. LC/MS (Cond. J2):RT=1.49 min. LC/MS Anal. Calcd. for [M+H]⁺ C₁₀H₉BrN₂: 237.00. found236.96.

EEDQ (1.67 g, 6.75 mmol) was added to a solution of Example J.9g2 (1.6g, 6.75 mmol) and M.4a (1.55 g, 6.75 mmol) in DCM (100 mL) and stirredfor 6 h. (Note: The dianiline was not completely soluble). The reactionmixture was diluted with DCM (1 vol) and washed with half sat'd NaHCO₃soln. Concentration gave a solid (2.5 g). LC/MS (Cond. J2): RT=3.07 min.LC/MS Anal. Calcd. for [M+H]⁺ C₂₁H₂₇BrN₃O₃: 448.13. found 448.11.

The crude solid (2.5 g, 5.58 mmol) was taken up in AcOH (200 mL) andstirred for 18 h at 60° C. Concentration under high vacuum removed thesolvent. The residue was taken up in DCM, washed with sat'd NaHCO₃ soln,and concentrated. The residue was charged (DCM) to a 80 g Thompsonsilica gel cartridge and gradient elution was performed from 15% to 100%B over 750 mL. (A/B Hex/EtOAc) to give Example J.9g (2.6 g). ¹H NMR(MeOD, 500 MHz, δ): 8.36-8.35 (m, 2H), 8.0 (d, J=9 Hz, 1H), 7.91 (dd,J=9, 2 Hz, 1H), 7.87 (d, J=9 Hz, 1H), 5.31-5.28 (m, 1H), 4.17 (br. s,1H), 2.59-2.56 (m, 1H), 2.39-2.31 (m, 2H) 1.86-1.83 (m, 1H), 1.52-1.19(m, 12H). LC/MS (Cond. J2): RT=2.57 min. LC/MS Anal. Calcd. for [M+H]⁺C₂₁H₂₅BrN₃O₂: 430.12. found 430.09.

Examples J.10-J.12

EDCI.HCl (2.35 g, 12.25 mmol) was added to a mixture of4-bromobenzene-1,2-diamine (2.078 g, 11.11 mmol), N-Boc-L-proline (2.311g, 10.74 mmol) and 1-hydroxybenzotriazole (1.742 g, 12.89 mmol) indichloromethane (40 mL), and stirred at ambient conditions for 19 h. Themixture was then diluted with dichloromethane, washed with water (2×),dried (brine; MgSO₄), filtered, and concentrated in vacuo to provide abrown foam. Acetic acid (40 mL) was added to the foam, and the mixturewas heated at 65° C. for 90 min. The volatile component was removed invacuo, and the residue was dissolved in ethyl acetate and washedcarefully with saturated NaHCO₃ solution (2×), and the organic phase wasdried (brine; MgSO₄), filtered, and concentrated in vacuo. The resultantcrude material was submitted to flash chromatography (silica gel; ethylacetate) to provide J.10 as a tan foam (2.5 g). ¹H NMR (DMSO-d₆, δ=2.5ppm, 400 MHz): 12.49-12.33 (four br s, 1H), 7.71 (d, J=2, 0.54H), 7.60(app br s, 0.46H), 7.50 (d, J=8.6, 0.45H), 7.40 (d, J=8.4, 0.55H), 7.26(m, 1H), 4.96-4.87 (m, 1H), 3.64-3.51 (m, 1H), 3.44-3.38 (m, 1H),2.38-2.21 (m, 1H), 1.99-1.85 (m, 3H), 1.39 (s, 3.7H), 1.06 (s, 5.3H).(Cond.-D2) LC/MS: Anal. Calcd. for [M+H]+ C₁₆H₂₁BrN₃O₂: 368.03. found:368.18.

J.10a

RT = 1.9 min (Cond.-J1) LC/MS: Anal. Calcd. for [M + Na]⁺C₁₆H₂₀BrN₃NaFO₂: 406.06; found: 406.06. J.10b

RT = 1.7 min (Cond.-D2) LC/MS: Anal. Calcd. for [M + Na]⁺C₁₇H₂₀BrN₃NaO₂: 400.06; found: 400.09 J.10c

RT = 1.9 min (Cond.-J1) LC/MS: Anal. Calcd. for [M + Na]⁺C₁₇H₂₀BrN₃NaFO₂: 418.06; found: 418.06. J.10d

RT = 2.0 min (Cond.-J2) LC/MS: Anal. Calcd. for [M + H]⁺ C₁₇H₂₃BrN₃O₂:380.10; found: 380.03.

4-Iodo-2-nitroaniline (35.2 g, 0.133 mol) was added in batches via anopen funnel over 25 min to a heated (65° C.) mixture of SnCl₂.2H₂O(106.86 g, 0.465 mol) and 12N HCl (200 ml). An additional 12N HCl (30ml) was added and the reaction mixture was heated at 65° C. for anadditional 1 h, and stirred at room temperature for 1 h. It was placedin a refrigerator for 15 h, and the precipitate was filtered. Theresultant solid was transferred into a flask containing water (210 ml),cooled (ice/water), and a solution of NaOH (aq) (35 g in 70 ml of water)was added to it over 10 min with stirring. The cooling bath was removed,and vigorous stirring was continued for 45 min. The mixture was filteredand the solid was washed with water and dried in vacuo to provide4-iodobenzene-1,2-diamine as a tan solid (25.4 g). The product was usedin the next step without further purification. ¹H NMR (DMSO-d₆, δ=2.5ppm, 500 MHz): 6.79 (d, J=2, 1H), 6.63 (dd, J=1.9, 8.1, 1H), 6.31 (d,J=8.1, 1H), 4.65 (br s, 2H), 4.59 (br s, 2H). LC/MS: Anal. Calcd. for[M+H]+ C₆H₈IN₂: 234.97. found: 234.9.

HATU (6.5 g, 17.1 mmol) was added to a solution of4-iodobenzene-1,2-diamine (4 g, 17.1 mmol),(S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (3.67 g, 17.1mmol), and Hunig's base (3 mL) in dimethylformamide (100 mL). Thereaction mixture was stirred for 4 h before being diluted with ethylacetate (300 mL) and washed with sat'd NaHCO₃, brine, and dried(Na₂SO₄). The aqueous phase was extracted twice more with ethyl acetateand combined with the initial organic extract prior to drying.Concentration gave a residue which was taken up in glacial acetic acid(100 mL) and heated at 65° C. for 2 h. The cooled mixture wasconcentrated in vacuo, diluted with ethyl acetate (300 mL) and 1N NaOHsolution (to pH=10), washed with brine, and dried (Na₂SO₄). The crudeproduct was applied applied to a 65 (i) Biotage silica gel cartridge.Segment 1. Hold 15% B for 450 mL; Segment 2. Gradient elution from 15%to 100% B over 4.5 L (A=hexane; B=ethyl acetate); Segment 3. Hold 100% Bfor 2.5 L to give J.11 tert-butyl2-(5-iodo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-(S)-carboxylate 7.0 g(99%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (br.s, 1H), 7.42 (d, J=8.2 Hz,1H), 7.34 (br. s, 1H), 4.97-4.84 (m, 1H), 3.6 (br. s, 1H), 3.44-3.40 (m,1H), 2.37-2.25 (m, 1H), 1.99-1.87 (m, 3H), 1.4/1.07 (s, 9H). LC(Cond.-D2): 2.1 min; LCMS: Anal. Calcd. for [M+H]⁺ C₁₆H₂₀IN₃O₂: 414.07.found: 414.08.

Unwashed 60% sodium hydride (48 mg, 1.21 mmol) was added in one portionto a stirred solution of J.11 tert-butyl2-(5-iodo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-(S)-carboxylate (500mg, 1.21 mmol) in dry dimethylformamide (10 mL) under nitrogen. Themixture was stirred 5 min before addition of SEM-C1 (0.21 mL, 1.21mmol), stirred for 3 h, quenched with sat'd ammonium chloride (1 mL),diluted with ethyl acetate (50 mL), and the organic phase was washedwith sat'd NaHCO₃ soln and brine. The aqueous phase was extracted twicemore with ethyl acetate and combined with the initial organic extractprior to drying. Concentration gave a residue applied which was applied(dichloromethane) to a 40 (i) Biotage silica gel cartridge. Segment 1.Hold 5% B for 150 mL; Segment 2. Gradient elution from 5% to 100% B over2.5 L (A=hexane; B=ethyl acetate) B to give regioisomeric products (SEMlocation) J.12 316 mg (48%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, J=5.8Hz, 1H), 7.54-7.49 (m, 2H), 5.77-5.64 (m, 2H), 5.20-5.11 (m, 1H),3.61-3.43 (m, 4H), 2.89-2.05 (m, 2H), 1.98-1.87 (m, 2H), 1.36/1.04 (s,9H), 0.91-0.81 (m, 2H), −0.06 (s, 9H). LC (Cond.-D2): RT=3.1 min; LRMS:Anal. Calcd. for [M+H]⁺ C₂₂H₃₄IN₃O₃Si: 544.15. found: 544.15.

Examples J.13-J.13f

Pd(Ph₃P)₄ (469 mg, 0.406 mmol) was added to a pressure tube containing amixture of J.7 (S)-tert-butyl2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4 g,10.22 mmol), bis(pinacolato)diboron (5.4 g, 21.35 mmol), potassiumacetate (2.6 g, 26.21 mmol) and 1,4-dioxane (80 mL). The reaction flaskwas purged with nitrogen, capped and heated (oil bath 80° C.) for 16hours. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo. The crude material was partitioned carefullybetween dichloromethane (150 mL) and an aqueous medium (50 mL water+10mL saturated NaHCO₃ solution). The aqueous layer was extracted withdichloromethane, and the combined organic phase was dried (MgSO₄),filtered, and concentrated in vacuo. The resulting material was purifiedwith flash chromatography (sample was loaded with eluting solvent;20-35% ethyl acetate/dichloromethane) to provide J.13 (S)-tert-butyl2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate,contaminated with pinacol, as an off-white dense solid; the relativemole ratio of J.13 to pinacol was about 10:1 (¹H NMR). The sampleweighed 3.9 g after ˜2.5 days exposure to high vacuum. ¹H NMR (DMSO-d₆,δ=2.5 ppm, 400 MHz): 12.22/11.94/11.87 (m, 1H), 7.79-7.50/7.34-7.27 (m,5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.27-1.77 (m,4H), 1.45-1.10 (m, 21H). LC (Cond.-J1): RT=1.64 min; LC/MS: Anal. Calcd.for [M+H]⁺ C₂₄H₃₅BN₃O₄: 440.27. found 440.23.

J.13a

RT = 1.6 min (Cond.-J1); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₄H₃₅BN₃O₄:440.27; found: 440.36. J.13b

RT = 1.6 min (Cond.-J1); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₅H₃₅BN₃O₄:452.27; found: 452.17. J.13c

RT = 1.9 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₇H₃₈BN₃O₄:480; found: 480. J.13d

RT = 1.7 (Cond.-J1) LCMS: Anal. Calcd. for [M + H]⁺ C₂₂H₃₃BN₃O₄ 414.25;found: 414.28. J.13e

RT = 2.1 (Cond.-D2) LCMS: Anal. Calcd. for [M + H]⁺ C₂₃H₃₃BN₃O₄ 426.29;found: 426.21. J.13f

RT = 2.46 (Cond.-D2) LCMS: Anal. Calcd. for [M + H]⁺ C₂₆H₃₇BN₃O₄ 466.28;found: 466.33.

Examples J.14-J.14f.1

The benzimidazole J.12 (250 mg, 0.46 mmol), boronic ester J.13c (217 mg,0.46 mmol), and NaHCO₃ (95 mg, 1.13 mmol) were dissolved in1,2-dimethoxyethane (4.5 mL) and water (1.1 mL) was added. The reactionmixture was evacuated and flushed with nitrogen (3×), Pd(Ph₃P)₄ (26 mg,0.022 mmol) was added, and the mixture heated (oil bath at 80° C.) in acapped pressure vessel for 14 h. After being cooled, the solution waspartitioned into ethyl acetate/water and the organic layer washed withsat'd NaHCO₃, brine, and dried (Na₂SO₄). Concentration gave a residuewhich was applied to a 25M Biotage SiO₂ column pre-equilibrated with 25%B (300 mL). Gradient elution; Segment 1: 25% B (60 mL); Segment 2:25-100% B (1440 mL); Segment 3: Hold at 100% (600 mL). A=Hexanes;B=ethyl acetate gave J.14, 101.1 mg (29%). ¹H NMR (500 MHz, DMSO-d₆) δ8.10-8.09 (m, 1H), 7.96/7.91 (s, 1H), 7.65-7.47 (m, 4H), 5.85-5.70 (m,2H), 5.12/5.14 (s, 1H), 4.83/4.73 (s, 1H), 3.62-3.54 (m, 4H), 3.48-3.26(m, 2H), 2.90 (br. s, 4H), 2.37-1.84 (m, 10H), 1.42/1.08 (s, 9H),1.37/1.06 (s, 9H), 0.92-0.83 (m, 2H), 0.06 (s, 9H). LC (Cond.-D2): 2.8min; LCMS: Anal. Calcd. for [M+H]⁺ C₄₃H₆₁N₆O₅Si 769.45. found: 769.43.HRMS: Anal. Calcd. for [M+H]⁺ C₄₃H₆₁N₆O₅Si: 769.4473. found 769.4484.

J.14a

RT = 2.71 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₇N₆O₅Si729.42; found: 729.43. HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₇N₆O₅Si:729.4160; found: 729.4188. J.14b

RT = 2.75 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₇N₆O₅Si729.42; found: 729.44. HRMS: Anal. Calcd. for [M + H]⁺ C₄₀H₅₇N₆O₅Si:729.4160; found: 729.4191. J.14c

RT = 1.6 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₆N₆O₄663.37; found: 663.46. HRMS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₆N₆O₄663.3653; found: 663.3648. J.14d

RT = 2.11 min, (Cond.-D2); Calcd for C₃₆H₄₅N₆O₄ [M + H]⁺ 625.35; found:625.42. HRMS: Calcd for C₃₆H₄₅N₆O₄ [M + H]⁺ 625.3497; found: 625.3486.J.14e

RT = 1.83 min, (Cond.-J1); Calcd for C₂₂H₂₅BrN₃O₂ [M + H]⁺ 442.12;found: 442.20. J.14e.1

RT = 2.40 min, (Cond.-D2); Calcd for C₂₆H₂₉BrN₃O₂ [M + H]⁺ 494.15;found: 494.14. J.14f

RT = 1.66 min, (Cond.-J1); Calcd for C₄₀H₄₇N₆O₄ [M + H]⁺ 675.36; found:675.52. J.14f.1

RT: 2.15 min, (Cond.-D1); Calcd for C₄₂H₄₉N₆O₄ [M + H]⁺ 701.38; found:701.35.

Examples J.14g-J.14g.1

Activated manganese dioxide (122 mg, 1.409 mmol) was added in oneportion to a stirred solution of J.14d (S)-tert-butyl2-(7-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate(88 mg, 0.141 mmol) in dry dichloromethane (2 mL). The suspension wasstirred for 14 h and additional manganese dioxide (1.5 g) was added. Thesuspension was stirred for 16 h and manganese dioxide (1.5 g) was addedagain and allowed to continue stirring for 24 h. The reaction mixturewas filtered through diatomaceous earth (Celite®), concentrated, andplaced on high vacuum for 1 h. There was isolated J.14g (85.0 mg, 92%)as a yellowish-orange solid. LCMS: 2.14 min (Cond.-D2) Calcd. forC₃₆H₄₃N₆O₄ [M+H]⁺623.33. found: 623.46. HRMS: Calcd for C₃₆H₄₃N₆O₄[M+H]⁺623.3340. found: 623.3327.

J.14g.1

RT: 2.20 min, (Cond.-D1); Calcd for C₄₂H₄₇N₆O₄ [M + H]⁺ 699.37; found:699.32.

Examples JB.1-JB.3

Glyoxal (2.0 mL of 40% in water) was added dropwise over 11 minutes to amethanol solution of NH₄OH (32 mL) and (S)-Boc-prolinal (8.56 g, 43.0mmol) and stirred at ambient temperature for 19 hours. The volatilecomponent was removed in vacuo and the residue was purified by a flashchromatography (silica gel, EtOAc) followed by a recrystallization(EtOAc, room temperature) to provide (S)-tert-butyl2-(1H-imidazol-2-yl)pyrrolidine-1-carboxylate (4.43 g) as a white fluffysolid. ¹H NMR (DMSO-d₆, 400 MHz): 11.68/11.59 (br s, 1H), 6.94 (s, 1H),6.76 (s, 1H), 4.76 (m, 1H), 3.48 (m, 1H), 3.35-3.29 (m, 1H), 2.23-1.73(m, 4H), 1.39/1.15 (s, 9H). RT=0.87 min (Cond.-JB.1) LC/MS: Anal. Calcd.for [M+H]⁺ C₁₂H₂₀N₃O₂: 238.16. found 238.22. The compound shown to havea 98.9 ee % when analyzed under the chiral HPLC conditions noted below.Column: Chiralpak AD, 10 um, 4.6×50 mm Solvent: 1.7% ethanol/heptane(isocratic) Flow rate: 1 mL/min Wavelength: either 220 or 256 nm.Relative retention time: 3.25 min (R), 5.78 minutes (S)

Iodine was (16.17 g, 63.7 mmol) was added to a solution of Example JB.1(6.87 g, 29.0 mmol) and sodium carbonate (9.21 g, 87 mmol) in dioxane(72 mL) and water (72 mL) at ambient temperature. The flask was coveredwith aluminum foil and stirred for 16 hours. The reaction mixture wasdiluted with EtOAc and a saturated aqueous solution of sodiumthiosulfate. The mixture was stirred for 15 minutes and the phases wereseparated. The layers were separated and the aqueous phase was extractedseveral times with ethyl acetate. The combined organic phases were dried(Na₂SO₄), filtered and concentrated in vacuo to afford (S)-tert-butyl2-(4,5-diiodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (12.5 g) as atan solid. ¹H NMR (500 MHz, MeOD) δ ppm 4.72-4.84 (m, 1H), 3.58-3.70 (m,1H), 3.43-3.54 (m, 1H), 2.36 (br s, 1H), 1.88-2.08 (m, 3H), 1.47 (br s,3H), 1.27 (br s, 6H). RT=1.40 min (Cond.-JB.1) LC/MS: Anal. Calcd. for[M+H]⁺ C₁₂H₁₇I₂N₃O₂: 488.94. Found; 489.96.

Sodium sulfite (10.31 g, 82 mmol) was added to a solution of ExampleJB.2 (4.0 g, 8.2 mmol) in ethanol (75 mL) and water (75 mL). Thesuspension was heated with an oil bath at 100° C. for 4 hours and at 90°C. for 16 h. The reaction was diluted with EtOAc and water. The layerswere separated and the aqueous layer was extracted several times withEtOAc. The combined organic phases were dried (brine, Na₂SO₄), filteredand concentrated in vacuo. The residue was purified by a flashchromatography (sample was dry loaded on silica gel and eluted with, 0to 40% ethyl acetate/CH₂Cl₂) to afford (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.17 g) as a whitesolid. ¹H NMR (500 MHz, MeOD) δ ppm 7.52-7.64 (m, 1H), 4.95-5.10 (m,1H), 3.57-3.70 (m, 1H), 3.47-3.57 (m, 1H), 2.37-2.55 (m, 1H), 1.94-2.10(m, 3H), 1.46 (s, 4H), 1.27 (s, 5H). RT=0.93 min (Cond.-JB.1) LC/MS:Anal. Calcd. for [M+H]⁺ C₁₂H₁₈IN₃O₂363.04. Found: 364.06.

Examples J.15-JB.4

A mixture of copper iodide (299.6 mg, 48.1 mmol) and Pd(PPh₃)₂Cl₂ (1.29g, 4.41 mmol) was added to a dimethylformamide (200 ml) solution of J.11(16.0 g, 38.7 mmol), (trimethylsilyl)acetylene (6.8 ml, 48.1 mmol), andtriethylamine (16 ml), and the reaction mixture was stirred at ˜25° C.for 19.5 h. The volatile component was removed in vacuo and a silica gelmesh was prepared from the residue and submitted to a flashchromatography (silica gel; eluting with 40% ethyl acetate/hexanes) toprovide alkyne J.15 as a tan foam (13.96 g). ¹H NMR (DMSO-d₆, δ=2.5 ppm,500 MHz): 12.52-12.38 (m, 1H), 7.62-7.41 (m, 2H), 7.24-7.19 (m, 1H),5.01-4.85 (m, 1H), 3.64-3.51 (m, 1H), 3.46-3.35 (m, 1H), 2.38-2.21 (m,1H), 2.07-1.81 (m, 3H), 1.39 (s, 4H), 1.04 (s, 5H), 0.23 (s, 9H).RT=2.09 min (Cond.-J1) LC/MS: Anal. Calcd. for [M+H]⁺ C₂₁H₃₀N₃O₂Si:384.21. found: 384.27.

J.15a

RT = 1.89 min, (Cond.-J1); Calcd for C₂₁H₂₉N₃O₂Si [M + H]⁺ 402.20;found: 402.26. J.15b

RT = 1.92 min, (Cond.-J1); Calcd for C₂₂H₃₀N₃O₂Si [M + H]⁺ 396.21;found: 396.22. J.15c

RT = 2.2 min, (Cond.-J1); Calcd for C₂₂H₂₉FN₃O₂Si [M + H]⁺ 414.20;found: 414.26. J.15d

RT = 1.70 min, (Cond.-J1); Calcd for C₂₅H₃₆N₃O₂Si [M + H]⁺ 438.26;found: 438.33. J.15d.1

RT = 1.70 min, (Cond.-J1); Calcd for C₂₂H₃₂N₃O₂Si [M + H]⁺ 398.23;found: 398.19. J.15e

RT = 2.43 min, (Cond.-D1); Calcd for C₂₆H₃₄N₃O₂Si [M + H]⁺ 448.24;found: 448.82. J.15f

LCMS: 2.51 min, (Cond.-D1); Calcd for C₂₆H₃₂N₃O₂Si (M + H)⁺ found:446.05. JB.4

LCMS: 1.5 min, (Cond.-JB.1); Calcd for C₁₇H₂₈N₃O₂Si (M + H)⁺ 334.20;found: 334.14.

Examples J.16-JB.5

Potassium carbonate (0.5526 g, 4 mmol) was added to solution of alkyneJ.15 (13.9 g, 36.2 mmol) in methanol (200 ml) and the mixture wasstirred at room temperature for 17 h. The volatile component was removedin vacuo, and the residue was partitioned between ethyl acetate andsaturated ammonium chloride (aq) solution, and the organic layer wasseparated and washed with brine, dried (MgSO₄), filtered, andconcentrated in vacuo to provide alkyne J.16 as a tan foam (9.3 g). ¹HNMR (DMSO-d₆, δ=2.5 ppm, 500 MHz): 12.58-12.30 (br s, 1H), 7.72-7.36(two overlapping app br s, 2H), 7.23 (d, J=8.1, 1H), 4.97-4.88 (m, 1H),4.02 (s, 1H), 3.64-3.52 (m, 1H), 3.44-3.36 (m, 1H), 2.40-2.20 (m, 1H),2.06-1.81 (m, 3H), 1.39 (s, 4H), 1.05 (s, 5H). LC/MS: Anal. Calcd. for[M+Na]⁺ C₁₈H₂₁N₃NaO₂: 334.15; found: 334.24.

J.16a

RT = 1.69 min, (Cond.-J1); Calcd for C₁₈H₂₀N₃O₂ [M + Na]⁺ 352.14; found:352.15. J.16b

RT = 1.40 min, (Cond.-J1); Calcd for C₁₉H₂₁N₃O₂ [M + Na]⁺ 346.15; found:346.19. J.16c

RT = 1.36 min, (Cond.-J1); Calcd for C₁₉H₂₀FN₃O₂ [M + Na]⁺ 364.14;found: 364.15. J.16d

RT = 1.30 min, (Cond.-J1); Calcd for C₂₂H₂₈N₃O₂ [M + H]⁺ 366.22; found:366.25. J.16d.1

RT = 2.74 min, (Cond.-J2); Calcd for C₁₉H₂₄N₃O₂ [M + H]⁺ 326.19; found:326.13. J.16e

LCMS: 1.88 min, (Cond.-D1) Calcd for C₂₃H₂₄N₃O₂ (M + H)⁺ 374.19; found:374.04. JB.5

LCMS: 0.88 min, (Cond.-JB-1) Calcd for C₁₀H₁₁N₃O₂ (M + H; −tBu)⁺ 206.10;found: 206.05.

Example J.16f

Example J.16f was obtained from Example J.16e according to the two stepprocedure described below. Deprotection as in the preparation of J.19 toformed an HCl salt which was coupled with cap-170 with HATU accordingthe preparation of J.21 below to give J.16f RT=1.59 min, (Cond.-D1);Calcd for C₂₇H₂₉N₄O₄ [M+H]⁺ 473.22. found: 473.06.

Example J.17-17.a

The ammonium hydroxide (4 mL) was added to a solution of (S)-prolinal(650 mg, 3.26 mmol) in tetrahydrofuran (15 mL) and stirred for 6 h at48° C. in a sealed pressure vessel. α-tosyl-(3-bromobenzyl) isocyanide(974 mg, 2.77 mmol) and piperazine (281 mg, 3.26 mmol) were added andthe reaction mixture stirred 18 h at at 48° C. After being cooled, thereaction mixture was diluted with ethyl acetate (200 mL) and washed withwater and brine and concentrated. The crude product was taken up indichloromethane and charged to a 40 g Thomson silica gel cartridge.Gradient elution was performed from 20-100% B over 750 mL gave J.17(S)-tert-butyl2-(5-(3-bromophenyl)-1H-imidazol-4-yl)pyrrolidine-1-carboxylate 413 mg(31%). ¹H NMR (CDCl₃, δ 500 MHz): 10.36/9.90 (br s, 1H), 7.75 (br s,1H), 7.53 (br. s, 2H), 7.38 (br. s, 1H), 7.24 (br. s, 1H), 5.11 (br. s,1H), 3.54 (br. s, 2H), 2.32/2.19 (m, 1H), 1.95-1.85 (m, 2H), 1.74 (s,1H), 1.45/1.18 (s, 9H). RT=1.7 (Cond.-J1) LC/MS: Anal. Calcd. for [M+H]⁺C₁₈H₂₃BrN₃O₂: 392.09. found: 392.13.

J.17a

RT = 1.7 min, (Cond.-J1); Calcd for C₁₈H₂₃BrN₃O₂ [M + H]⁺ 392.09; found:392.13.

Examples J.18-JB.6

Copper iodide (9.8 mg, 0.051 mmol) and Pd(PPh₃)₄ (59.4 mg, 0.051 mmol)were added to a nitrogen purged solution of J.16 (S)-tert-butyl2-(5-ethynyl-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (160 mg,0.514 mmol) and J.7 (S)-tert-butyl2-(4-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (171 mg,0.437 mmol) containing Et₃N (0.2 mL) in dimethylformamide (3 mL) and thereaction mixture stirred at room temperature for 48 h. The volatilecomponent was removed in vacuo and the residue was applied(dichloromethane) to 20 g Thomson column and eluted with 50-100% B over500 mL (A/B dichloromethane/20% methanol in ethyl acetate) to provideJ.18; 87 mg (26%). ¹H NMR (CDCl₃, δ, 500 MHz): 10.97-10.51 (m, 2H), 7.9(s, 0.41H), 7.75 (d, J=8.2, 1.26H), 7.69-7.66 (m, 0.55H), 7.59 (s,0.54H), 7.54-7.51 (m, 1.85H), 7.42-7.32 (m, 2H), 7.25 (s, 1H), 7.22 (br.s, 0.32) (br.s, 1H), 4.99-4.94 (m, 1H), 3.31 (br.s, 3H), 3.04/2.92 (br.s, 2H), 2.19-2.15 (m, 3H), 2.03-1.95 (m, 2H), 1.62/1.50 (br s, 20H). LC(Cond-J1): 1.6 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₃₆H₄₃N₆O₄: 623.34.found: 623.52; HRMS: Anal. Calcd. for [M+H]⁺ C₃₆H₄₃N₆O₄: 623.3340.found: 623.3344.

J.18.1

RT = 1.4 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₇N₆O₄651.36; found: 651.46. J.18.2

RT = 1.34 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₄N₇O₄662.35; found: 662.35. J.18a

RT = 1 6 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₃N₆O₄647.33; found: 647.39. J.18b

RT = 1.57 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₂FN₆O₄665.33; found: 665.49. J.18c

RT = 1.42 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₂FN₆O₄665.33; found: 665.49. J.18d

RT: 2.27 min, (Cond.-D2); Calcd for C₃₈H₄₅N₆O₄ [M + H]⁺ 649.35; found:649.49. HRMS: Calcd for C₃₈H₄₅N₆O₄ [M + H]⁺ 649.3497; found: 649.3484.J.18e

RT: 2.31 min, (Cond.-D2); Calcd for C₃₈H₄₃N₆O₄ [M + H]⁺ 647.33; found:647.46. HRMS: Calcd for C₃₈H₄₃N₆O₄ [M + H]⁺ 647.3340; found: 647.3328.J.18f

RT: 1.61 min, (Cond.-J1); Calcd for C₃₈H₄₄FN₆O₄ [M + H]⁺ 667.34; found:667.46. J.18g

RT: 1.64 min, (Cond.-J1); Calcd for C₃₈H₄₂FN₆O₄ [M + H]⁺ 665.33; found:665.49. J.18h

RT: 1.44 min, (Cond.-J1); Calcd for C₄₀H₄₅N₆O₄ [M + H]⁺ 673.35; found:673.43. J.18i

RT: 1.48 min, (Cond.-J1); Calcd for C₄₀H₄₃N₆O₄ [M + H]⁺ 670.34; found:670.46. J.18i.1

RT: 2.03 min, (Cond.-D1); Calcd for C₄₃H₄₃N₆O₄ [M + H]⁺ 707.34; found:707.28. J.18i.2

RT: 2.10 min, (Cond.-D1); Calcd for C₄₃H₄₁N₆O₄ [M + H]⁺ 705.32; found:705.19. J.18i.3

RT = 1.92 min (Cond.-D1); LCMS: Calcd for C₄₄H₄₈N₇O₆ (M + H)⁺ 770.37;found: 770.29. J.18j

RT: 1.62 min, (Cond.-J1); Calcd for C₄₀H₄₄FN₆O₄ [M + H]⁺ 691.34; found:691.46. J.18k

RT: 1.66 min, (Cond.-J1); Calcd for C₄₀H₄₂FN₆O₄ [M + H]⁺ 689.33; found:689.43. J.18k.1

RT: 3.44 min, (Cond.-J2); Calcd for C₄₀H₄₇N₆O₄ [M + H]⁺ 675.37; found:675.33 J.18l

RT = 1.67 min, (Cond.-J1); Calcd for C₃₆H₄₃N₆O₄ [M + H]⁺ 623.34; found:623.46. J.18m

RT = 1.67 min, (Cond.-J1); Calcd for C₃₆H₄₃N₆O₄ [M + H]⁺ 623.34; found:623.46. JB.6

RT = 1.33 min, (Cond.-JB.1); Calcd for C₃₆H₄₃N₆O₄ [M + H]⁺ 623.34;found: 623.24.

Examples J.19-JB.7

Example J.14 (85 mg, 0.11 mmol) was dissolved in methanol (1 mL) and 4NHCl/Dioxane (5 mL) was added and the reaction was stirred 16 hr. Thesolvents were removed in vacuo, and the tetra HCl salt J.19 was exposedto high vacuum for 18 h. LC (Cond-D2): 1.4 min; LRMS: Anal. Calcd. for[M+H]⁺ C₂₇H₃₁N₆: 439.26. found: 439.29. HRMS: Anal. Calcd. for [M+H]⁺C₂₇H₃₁N₆: 439.2610. found 439.2593.

J.19a

RT = 1.34 min (Cond.-D2) LCMS: Anal. Calcd. for [M + H]⁺ C₂₄H₂₇N₆:399.23; found: 399.24. HRMS: Anal. Calcd. for [M + H]⁺ C₂₄H₂₇N₆:399.2297; found: 399.2316. J.19b

RT = 1.46 min (Cond.-D2) LCMS: Anal. Calcd. for [M + H]⁺ C₂₄H₂₇N₆:399.23; found: 399.24. HRMS: Anal. Calcd. for [M + H]⁺ C₂₄H₂₇N₆:399.2297; found: 399.2298. J.19c

RT = 1.13 min (Coad.-J1) LCMS: Anal. Calcd. for [M + H]⁺ C₂₉H₃₀N₆:463.26; found: 463.38. J.19d

RT = 1.27 min, (Cond.-D2) LCMS: Calcd for C₂₆H₂₉N₆ [M + H]⁺ 425.24;found: 425.28. HRMS: Calcd for C₂₆H₂₉N₆ [M + H]⁺ 425.2448; found:425.2444. J.19e

RT = 1.30 min, (Cond.-J1) LCMS: Calcd for C₃₀H₃₁N₆ [M + H]⁺ 475.26;found: 475.25. J.19f

RT = 1.46 min, (Cond.-D2) LCMS: Calcd for C₂₆H₂₇N₆ [M + H]⁺ 423.23;found: 423.31. HRMS: Calcd for C₂₆H₂₇N₆ [M + H]⁺ 423.2292; found:423.2287. J.19f.1

RT: 1.73 min, (Cond.-D1); Calcd for C₃₂H₃₁N₆ [M + H]⁺ 499.26; found:499.22. J.20

RT = 1.18 min, (Cond.-J1) LCMS: Calcd for C₂₆H₂₇N₆ [M + H]⁺ 423.23;found: 423.24. J.20.1

RT = 0.99 min (Cond.-J1); LCMS Calcd for C₂₈H₃₁N₆ (M + H)⁺ 451.25;found: 451.28. J.20.2

RT = 0.98 min (Cond.-J1); LCMS Calcd for C₂₈H₂₈N₇ (M + H)⁺ 462.24;found: 462.24. J.20a

RT = 1.21 min, (Cond.-J1) LCMS: Calcd for C₂₈H₂₇N₆ [M + H]⁺ 447.23;found: 447.18. J.20b

RT = 1.04 min, (Cond.-J1) LCMS: Calcd for C₂₈H₂₆FN₆ [M + H]⁺ 465.21;found: 465.28. J.20c

RT = 1.07 min, (Cond.-J1) LCMS: Calcd for C₂₈H₂₆FN₆ [M + H]⁺ 465.21;found: 465.28. J.20d

RT = 1.60 min, (Cond.-D2) LCMS: Calcd for C₂₈H₂₉N₆ [M + H]⁺ 449.24;found: 449.28. J.20e

RT = 1.78 min, (Cond.-D2) LCMS: Calcd for C₂₈H₂₇N₆ [M + H]⁺ 447.23;found: 447.25. J.20f

RT = 1.07 min, (Cond.-J1) LCMS: Calcd for C₂₈H₂₈FN₆ [M + H]⁺ 467.24;found: 467.25. J.20g

RT = 1.17 min, (Cond.-J1) LCMS: Calcd for C₂₈H₂₆FN₆ [M + H]⁺ 465.22;found: 465.28. J.20g.1

RT = 1.43 min, (Cond.-D1) LCMS: Calcd for C₃₀H₂₉N₆ [M + H]⁺ 473.25;found: 473.13. J.20h

RT = 1.09 min, (Cond.-J1) LCMS: Calcd for C₃₀H₂₇N₆ [M + H]⁺ 471.23;found: 471.25. J.20h.1

RT: 1.60 min, (Cond.-D1); Calcd for C₃₉H₄₀N₇O₄ [M + H]⁺ 670.32; found:670.24. J.20h.2

RT: 1.77 min, (Cond.-D1); Calcd for C₃₈H₃₃N₆O₂ [M + H]⁺ 605.27; found:605.20. J.20i

RT = 1.09 min, (Cond.-J1) LCMS: Calcd for C₃₀H₂₈FN₆ [M + H]⁺ 491.24;found: 491.25. J.20j

RT = 1.17 min, (Cond.-J1) LCMS: Calcd for C₃₀H₂₆FN₆ [M + H] + 489.22;found: 489.22. J.20j.1

RT = 2.73 min, (Cond.-J2) LCMS: Calcd for C₃₀H₃₁N₆ [M + H]⁺ 475.26;found: 475.17. J.20k

RT = 1.0 min (Cond.-J1) LCMS: Calcd for C₂₆H₂₇N₆ [M + H]⁺ 423.23; found:423.24. J.20l

RT = 1.01 min (Cond.-J1) LCMS: Calcd for C₂₆H₂₇N₆ [M + H]⁺ 423.23;found: 423.31. JB.7

RT = 1.0 min (Cond.-J1) LCMS: Calcd for C₂₆H₂₇N₆ [M + H]⁺ 423.23; found:423.17.

Examples J.21-JB.12

HATU (60 mg, 0.16 mmol) was added to a rapidly stirred solution ofexample J.19 (38.18 mg, 0.075 mmol), N-methoxycarbonyl-L-valine (26.2mg, 0.15 mmol), and Hunig's base (0.095 mL, 0.54 mmol) indimethylformamide (1.5 mL). The reaction mixture was stirred for 2 h andthe solvent was removed under purge of nitrogen. The residue was dilutedwith methanol and subjected to prep. HPLC (Phenomenex LUNA C18 (30×100mm); 5%-100% B over 40 min; Flow Rate=40 mL/min; Wavelength=220 nm;Solvent A=0.1% TFA in 10% methanol/90% water; Solvent B=0.1% TFA in 90%methanol/10% water) to give the bis TFA salt of J.21, 17.6 mg (24%). ¹HNMR (500 MHz, DMSO-d₆) δ 7.91-7.84 (m, 1H), 7.72-7.57 (series m, 5H),7.30-6.8 (m, 2H), 5.50-5.17 (series m, 4H), 4.20 (m, 1H), 4.10 (br. s,1H), 3.34-3.25 (m, 6H), 3.17 (s, 6H), 3.14-2.90 (series m, 4H),2.23-2.20 (m, 2H), 2.13-1.93 (m, 8H), 1.32-1.03 (m, 12H). LC (Cond.-D2):1.8 min; LCMS: Anal. Calcd. for [M+H]⁺ C₄₁H₅₃N₈O₆ 753.41. found: 753.55.HRMS: Anal. Calcd. for [M+H]⁺ C₄₁H₅₃N₈O₆ 753.4088. found: 753.4108.

J.21a

RT = 2.1 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₅₁H₆₁N₈O₂:817.49; found: 817.63. HRMS: Anal. Calcd. for [M + H]⁺ C₅₁H₆₁N₈O₂:817.4917; found: 817.4927. J.22

RT = 1.88 min (Cond.-D2) LCMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₉N₈O₆:713.38; found: 713.31. HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₉N₈O₆:713.3775; found: 713.3804. J.22a

RT = 1.65 min (Cond.-D2) LCMS: Anal. Calcd. for [M + H]⁺ C₄₈H₅₆N₈O₂:777.46; found: 777.48. HRMS: Anal. Calcd. for [M + H]⁺ C₄₈H₅₆N₈O₂:777.4604; found: 777.4636. J.22b

RT = 1.99 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₄₄H₄₅N₈O₆:781.35; found: 781.37. HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₄₅N₈O₆:781.3462; found: 781.3483. J.23

RT = 1.92 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₉N₈O₆:713.38; found: 713.40. HRMS: Anal. Calcd. for [M + H]⁺ C₃₈H₄₉N₈O₆:713.3804; found: 713.3798. J.23a

RT = 1.72 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₄₈H₅₆N₈O₂:777.46; found: 777.48. HRMS: Anal. Calcd. for [M + H]⁺ C₄₈H₅₆N₈O₂:777.4604; found: 777.4579. J.23b

RT = 2.02 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₄₄H₄₅N₈O₆:781.35; found: 781.37. HRMS: Anal. Calcd. for [M + H]⁺ C₄₄H₄₅N₈O₆:781.3462; found: 781.3497. J.24

RT = 1.5 min (Cond.-J1); 87%, LCMS: Calcd for C₄₃H₅₃N₈O₆ (M + H)⁺777.41; found: 777.49. HRMS: Calcd for C₄₃H₅₃N₈O₆ (M + H)⁺ 777.4083;found: 777.4088. J.25

RT = 1.83 min (Cond.-D2); LCMS: 95%, Calcd for C₄₀H₅₁N₈O₆ (M + H)⁺739.39; found: 739.59. HRMS: Calcd for C₄₀H₅₁N₈O₆ (M + H)⁺ 739.3926;found: 739.3916. J.25.a

RT = 1.58 min (Cond.-D2); LCMS: Calcd for C₅₀H₅₉N₈O₂ (M + H)⁺ 803.47;found: 803.65. HRMS: Calcd for C₅₀H₅₉N₈O₂ (M + H)⁺ 803.4755; found:803.4749. J.26

RT = 1.51 min (Cond.-J1); LCMS Calcd for C₄₄H₅₃N₈O₆ (M + H)⁺ 789.41;found: 789.55. J.27

RT = 1.94 min (Cond.-D2); LCMS: 95%, Calcd for C₄₀H₄₉N₈O₆ (M + H)⁺737.38; found: 737.56. HRMS: Calcd for C₄₀H₄₉N₈O₆ (M + H)⁺ 737.3770;found: 737.3756. J.27a

RT = 1.67 min (Cond.-D2); LCMS: Calcd for C₅₀H₅₇N₈O₂ (M + H)⁺ 801.46;found: 801.68. HRMS: Calcd for C₅₀H₅₇N₈O₂ (M + H)⁺ 801.4599; found:801.4592. J.27b

RT = 1.94 min (Cond.-D1); LCMS: Calcd for C₄₆H₅₃N₈O₆ (M + H)⁺ 813.41;found: 813.46. J.27c

RT = 2.01 min (Cond.-D1); LCMS: Calcd for C₅₂H₄₉N₈O₆ (M + H)⁺ 881.38;found: 881.37. J.28

RT = 1.46 min (Cond.-J1); LCMS Calcd for C₄₀H₄₉N₈O₆ (M + H)⁺ 737.38;found: 737.42. HRMS: Calcd for C₄₀H₄₉N₈O₆ (M + H)⁺ 737.3770; found:737.3774. J.28a

RT = 1.30 min (Cond.-J1); LCMS Calcd for C₅₀H₅₇N₈O₂ (M + H)⁺ 801.46;found: 801.62. HRMS: Calcd for C₅₀H₅₇N₈O₂ (M + H)⁺ 801.4599; found:801.4585. J.28a.1

RT = 1.29 min (Cond.-J1); LCMS Calcd for C₄₂H₅₃N₈O₆ (M + H)⁺ 765.41;found: 765.49. J.28a.2

RT = 1.22 min (Cond.-J1); LCMS Calcd for C₄₂H₅₀N₉O₆ (M + H)⁺ 776.39;found: 776.42. J.28b

RT = 1.25 min (Cond.-J1); LCMS Calcd for C₄₂H₄₉N₈O₆ (M + H)⁺ 761.38;found: 761.49. J.28c

RT = 1.44 min (Cond.-J1); LCMS Calcd for C₄₂H₄₈FN₈O₆ (M + H)⁺ 779.37;found: 779.45. J.28d

RT = 1.30 min (Cond.-J1); LCMS Calcd for C₄₂H₄₈FN₈O₆ (M + H)⁺ 779.37;found: 779.45. J.28e

RT = 2.02 min (Cond.-D2); 95%, Calcd for C₄₂H₅iN₈O₆ (M + H)⁺ 763.39;found: 763.59. HRMS: Calcd for C₄₂H₅₁N₈O₆ (M + H)⁺ 763.3926; found:763.3918. J.28e.1

RT = 1.97 min (Cond.-D1); LCMS: Calcd for C₄₈H₄₇N₈O₆ (M + H)⁺ 831.43;found: 831.36. J.28f

RT = 2.10 min (Cond.-D2); 95%, Calcd for C₄₂H₄₉N₈O₆ (M + H)⁺ 761.38;found: 761.55. HRMS: Calcd for C₄₂H₄₉N₈O₆ (M + H)⁺ 761.3770; found:761.3765. J.28f.1

RT = 1.95 min (Cond.-D1); LCMS: Calcd for C₄₈H₄₅N₈O₆ (M + H)⁺ 829.35;found: 829.45. J.28g

RT = 1.46 min (Cond.-J1); LCMS Calcd for C₄₂H₅₀FN₈O₆ (M + H)⁺ 781.39;found: 781.49. J.28h

RT: 1.52 min, (Cond.-J1); Calcd for C₄₂H₄₈FN₈O₆ [M + H]⁺ 779.37; found:779.52. J.28h.1

RT = 1.83 min(Cond.-D1); LCMS: Calcd for C₄₄H₅₁N₈O₆ (M + H)⁺ 787.23;found: 787.40. J.28h.2

RT = 1.92 min (Cond.-D1); LCMS: Calcd for C₅₀H₄₇N₈O₆ (M + H)⁺ 855.36;found: 855.21. J.28i

RT: 1.34 min, (Cond.-J1); Calcd for C₄₄H₄₉N₈O₆ [M + H]⁺ 785.38; found:785.55. J.28i.1

RT = 2.01 min (Cond.-D1); LCMS: Calcd for C₅₀H₄₅N₈O₆ (M + H)⁺ 853.35;found: 853.25. J.28i.2

RT = 2.14 min (Cond.-D1); LCMS: Calcd for C₅₀H₅₅F₂N₈O₆ (M + H)⁺ 937.40;found: 937.46. J.28i.3

RT = 2.83 min (Cond.-D1); LCMS: Calcd for C₄₈H₅₃N₈O₈ (M + H)⁺ 869.40;found: 869.35. J.28i.4

RT = 1.81 min (Cond.-D1); LCMS: Calcd for C₄₆H₅iN₈O₇ (M + H)⁺ 827.39;found: 827.26. J.28j

RT: 1.49 min, (Cond.-J1); Calcd for C₄₄H₅₀FN₈O₆ [M + H]⁺ 805.39; found:805.55. J.28k

RT: 1.54 min, (Cond.-J1); Calcd for C₄₄H₄₈FN₈O₆ [M + H]⁺ 803.37; found:803.58. J.28k. 1

RT: 2.01 min, (Cond.-D1); Calcd for C₄₅H₄₄N₇O₅ [M + H]⁺ 762.34; found:762.16. J.28l

RT = 1.46 min (Cond.-J1); LCMS Calcd for C₄₀H₄₉N₈O₆ (M + H)⁺ 737.38;found: 737.56. HRMS: Calcd for C₄₀H₄₉N₈O₆ (M + H)⁺ 737.3770; found:737.3760. J.28m

RT = 1.36 min (Cond.-J1); LCMS Calcd for C₅₀H₅₇N₈O₂ (M + H)⁺ 801.46;found: 801.62. HRMS: Calcd for C₅₀H₅₇N₈O₂ (M + H)⁺ 801.4599; found:801.4597. J.28n

RT = 1.43 min (Cond.-J1); LCMS Calcd for C₄₀H₄₉N₈O₆ (M + H)⁺ 737.38;found: not apparent. HRMS: Calcd for C₄₀H₄₉N₈O₆ (M + H)⁺ 737.3770;found: 737.3759. J.28o

RT: 1.88 min, (Cond.-J2); Calcd for C₄₄H₅₃N₈O₆ [M + H]⁺ 789.41; found:789.36. J.28p

RT: 1.76 min, (Cond.-J2); Calcd for C₄₈H₅₇N₈O₈ [M + H]⁺ 873.43; found:873.43. JB.8

RT: 1.17 min, (Cond.-JB.1); Calcd for C₄₀H₄₉N₈O₆ [M + H]⁺ 737.38; found:737.31. JB.8.1

RT: 1.23 min, (Cond.-JB.1); Calcd for C₄₀H₄₉N₈O₆ [M + H]⁺ 737.38; found:737.33. JB.9

RT: 1.39 min, (Cond.-JB.1); Calcd for C₃₆H₄₁N₈O₆ [M + H]⁺ 681.32; found:681.21. JB.10

RT: 1.08 min, (Cond.-JB.1); Calcd for C₄₀H₄₉N₈O₈ [M + H]⁺ 769.37; found:769.31. JB.11

RT: 1.33 min, (Cond.-JB.1); Calcd for C₄₆H₄₅N₈O₆ [M + H]⁺ 805.35; found:805.27. JB 12

RT: 1.35 min, (Cond.-JB.1); Calcd for C₅₂H₅₆N₈O₂ [M + H]⁺ 825.46; found:825.34.

Examples J.28q-JB.13

A solution of Example J.28k.1 (286.6 mg, 0.376 mmol) in MeOH (2 mL) wasadded to a stirred suspension of 20% palladium hydroxide on carbon (52.8mg, 0.376 mmol) and potassium carbonate (104 mg, 0.752 mmol) in MeOH (4mL) under an atmosphere of nitrogen. The flask was evacuated and chargedwith hydrogen (3×; balloon, 14 psi) and stirred for 3 h. Note:Significant amounts of N-methylated product form if allowed to go over 3h. The mixture was filtered over celite, and the celite pad washed withMeOH (100 mL), methylene chloride (50 mL), and MeOH (100 mL) again. Thefiltrate was concentrated and placed under high vacuum for 0.5 h beforeit was taken up in MeOH and passed through a nylon syringe frit (toremove traces of catalyst). Example, J.28q was obtained (202 mg, 85%yield) as a yellow solid. RT: 1.62 min, (Cond.-D1); Calcd for C₃₇H₄₂N₇O₂[M+H]⁺ 632.34. found: 632.21.

10% Pd/C (50 mg, 0.470 mmol) was added in one portion to a suspension ofa TFA salt of Example JB.6 (100 mg, 0.118 mmol) in MeOH (10 mL). Thereaction mixture was purged with hydrogen and stirred under a balloon ofhydrogen overnight at rt. The reaction mixture was filtered throughCelite and concentrated. The residue was purified by prep HPLC (WatersSunfire C18 column 30×150 mm 5 u eluted with a gradient of 10 to 100%ACN−Water+0.1% TFA) to yield a TFA salt of tert-butyl(2S)-2-(4-(2-(4-(2-((2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethyl)-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate(70 mg) as a white solid. ¹H NMR (500 MHz, MeOD) δ ppm 7.95 (d, J=9.5Hz, 1H), 7.85 (d, J=9.2 Hz, 2H), 7.66 (br s, 2H), 7.31-7.44 (m, 2H),7.26 (s, 0.5H), 7.14 (s, 0.5H), 5.29 (br s, 1H), 5.04 (br s, 1H),3.73-3.82 (m, 1H), 3.64 (br s, 2H), 3.55 (br s, 1H), 3.02-3.15 (m, 4H),2.56-2.70 (m, 1H), 2.41-2.55 (m, 1H), 2.24 (br s, 1H), 2.08-2.18 (m,2H), 2.03 (br s, 3H), 1.49 (d, J=7.9 Hz, 9H), 1.26 (br s, 4.5H), 1.22(br s, 4.5H). RT: 1.16 min, (Cond.-JB-1); Calcd for C₃₆H₄₆N₆O₄ [M+H]⁺627.37. found: 627.31[M+H]⁺.

Examples J.28r-JB.15

J.28r

RT = 1.78 min (Cond.- D1); LCMS: Calcd for C₄₄H₅₃N₈O₆ (M + H)⁺ 789.41;found: 789.24. J.28s

RT = 1.67 min (Cond.- D1); LCMS: Calcd for C₄₆H₅₅N₈O₇ (M + H)⁺ 831.42;found: 831.26. JB.14

RT = 0.82 min (Cond.-JB-1); LC MS: Calcd for C₂₆H₃₁N₆ (M + H)⁺ 427.26;found: 427.28. JB.15

RT = 1.06 min (Cond.-JB-1); LC MS: Calcd for C₄₀H₅₆N₆O₆ (M + H)⁺ 741.41;found: 741.39.

Examples M5-M9

Example M.5 was prepared from L-proline according to the proceduredescribed in Gudasheva, et al. Eur. J. Med. Chem. 1996, 31, 151.

EDCI.HCl (1.76 g, 9.22 mmol) was added to a mixture of4-bromobenzene-1,2-diamine (1.50 g, 8.03 mmol), M.5 (1.88 g, 8.06 mmol)and 1-hydroxybenzotriazole (1.31 g, 9.70 mmol) in dichloromethane (30mL), and stirred at ambient conditions for 19 h. The mixture was thendiluted with dichloromethane, washed with water (2×), dried (brine;MgSO₄), filtered, and concentrated in vacuo to provide a brown foam.Acetic acid (30 mL) was added to the foam, and the mixture was heated at65° C. for 90 min. The volatile component was removed in vacuo, and theresidue was dissolved in ethyl acetate and washed carefully withsaturated NaHCO₃ solution (2×), and the organic phase was dried (brine;MgSO₄), filtered, and concentrated in vacuo. The resultant crudematerial was submitted to flash chromatography (silica gel; ethylacetate) to provide Example M.6 as a tan foam (1.67 g). ¹H NMR (CDCl₃,δ=7.24 ppm, 500 MHz): 10.71/10.68 (overlapping br s, 1H), 7.85 (s,0.48H), 7.56 (d, J=8.6, 0.52H), 7.50 (s, 0.52H), 7.35-7.22 (m, 6.48H),5.38 (app br d, J=8.1, 1H), 3.73 (d, J=15.7, 1H), 3.67 (d, J=15.6, 1H),3.64-3.51 (m, 2H), 3.12-3.04 (m, 1H), 2.41-2.28 (m, 1H), 2.20-2.08 (m,2H). LC/MS: Anal. Calcd. for [M+H]⁺ C₁₉H₁₈BrN₃O: 386.07. found: 386.10.

Pd(Ph₃P)₂Cl₂ (13.3 mg, 0.019 mmol) was added to a mixture of M.6 (152.9mg, 0.40 mmol), 4-ethynylaniline (69.6 mg, 0.59 mmol), and Et₃N (2.20mL) in dimethylformamide (2.0 mL) and the reaction was heated to 50° C.for 8.5 hr. The volatile component was removed in vacuo and the residuewas submitted to flash chromatography (0-30% methanol/dichloromethane),then further purified on reverse phase HPLC (methanol/water/TFA) toafford the TFA salt of M.7 (50 mg). LC/MS: Anal. Calcd. for [M+H]⁺C₂₇H₂₅N₄O: 421.2. Found 421.21.

Dichloromethane (3.0 mL) was added to a mixture of M.7 (57.0 mg, 0.14mmol), (S)-1-acetylpyrrolidine-2-carboxylic acid (23.3 mg, 0.15 mmol)and EEDQ (39.0 mg, 0.16 mmol) and stirred at ambient conditions for 16hr. The volatile components were removed in vacuo, and the residue wasdissolved in methanol and subjected to a reverse phase HPLC purification(methanol/water/TFA), followed by free-basing (SCX column; methanolwash; 2.0 M ammonia/methanol elution) and flash chromatographypurification (5-15% methanol/ethyl acetate) to afford M.8 as a brownsolid (38.0 mg). LC/MS: Anal. Calcd. for [M+H]⁺ C₃₄H₃₄N₅O₃: 560.27.found: 560.28.

M.9

LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₃₇N₅O₃: 636.30; found: 636.29.

Examples M.10-M.11

A mixture of M.8 (24.0 mg, 0.04 mmol) and Pd/C (10%, 14.1 mg) inmethanol (3.0 mL) was stirred under a balloon of H₂ (1 atm) for 3 hr.The suspension was filtered through a pad of diatomaceous earth(Celite®) and concentrated in vacuo to afford M.10 as an off-white foam(22.0 mg). LC/MS: Anal. Calcd. for [M+H]⁺ C₃₄H₃₈N₅O₃: 564.30. found:564.43.

M.11

LC/MS: Anal. Calcd. for [M + H]⁺ C₄₀H₄₂N₅O₃: 640.33; found: 640.35.

Examples J.29-J.32a

N-(4-(2-Chloroacetyl)-2-nitrophenyl)acetamide (25.7 g, 0.1 mol) wassuspended in 250 mL of 3N HCl and heated at 80° C. in 1 L pressurevessel for 20 h. After being cooled to room temperature,1-(4-amino-3-nitrophenyl)-2-chloroethanone.HCl (23.2 g, 92%) wasisolated by vacuum filtration as a bright yellow solid. The salt (23.2g, 0.092 mol) was suspended in methanol (600 mL) and tin chloridedihydrate (65 g, 0.29 mol) was added in one portion. The mixture washeated at 70° C. for 14 h while being vigorously stirred. An additional20 g of tin chloride dihydrate was added and the reaction stirred 8 h.The solvent was removed by rotory evaporation and the residue was takenup in ethyl acetate/NaHCO₃ soln (caution: much carbon dioxideevolution). The precipitated salts were removed by filtration and theorganic layer was separated. The aqueous layer was extracted twice more(ethyl acetate) and the combined organic layers were washed with brine,dried (Na₂SO₄) and concentrated to ¼ volume.2-Chloro-1-(3,4-diaminophenyl)ethanone, J.29, 10.03 g (59%) was isolatedby vacuum filtration as a brick red solid. ¹H NMR (400 MHz, DMSO-d₆) δ:8.17 (dd, J=8.3, 2.3 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 6.51 (d, J=8.0 Hz,1H), 5.57 (br. s, 2H), 4.85 (s, 2H), 4.78 (br. s, 2H). LC (Cond.-D2):0.65 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₈H₁₀ClN₂O: 185.05. found:185.02. HRMS: Anal. Calcd. for [M+H]⁺ C₈H₁₀ClN₂O: 185.0482. found:185.0480. The reaction was repeated to supply more material.

HATU (38.5 g, 101.3 mmol) was added portion wise to a vigorously stirredsolution of J.29 (17.0 g, 92 mmol), N-Boc-L-proline (19.82 g, 92 mmol),and Hunig's base (17.6 mL, 101.3 mmol) in dimethylformamide (200 mL).After 6 h, the reaction mixture was concentrated in vacuo to removesolvent and the residue was taken up in ethyl acetate, washed withsaturated NaHCO₃ solution, brine, and dried (Na₂SO₄). Concentrationyielded a viscous brown oil which was taken up in glacial acetic acid(100 mL) and heated at 60° C. for 20 h. The solvent was removed in vacuoand the residue was taken up in ethyl acetate, washed with saturatedNaHCO₃ solution (adjust with 1N NaOH soln until pH=9), brine, and dried(Na₂SO₄). The residue obtained upon concentration was pre-adsorbed ontoSiO₂ (dichloromethane) and subjected to flash chromatographysuccessively eluting with 50%, 75%, 100% ethyl acetate/hexanes to giveJ.30 (S)-tert-Butyl2-(6-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate22.37 g (67%) was obtained as a yellow foam. ¹H NMR (400 MHz, DMSO-d₆)δ: 8.20 (s, 1H), 7.81 (dd, J=8.3, 2.3 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H),5.24 (s, 2H), 4.99/4.93 (s, 1H), 3.60 (br. s, 1H), 3.46-3.41 (m, 1H),2.36-2.30 (m, 1H), 2.01-1.89 (m, 3H), 1.39/1.06 (s, 9H). LC (Cond.-D2):1.85 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₃ClN₃O₃: 364.14. found:364.20. HRMS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₃ClN₃O₃: 364.1428. found:364.1427.

Sodium azide (1.79 g, 27.48 mmol) was added in one portion to a solutionof J.30 (S)-tert-butyl2-(6-(2-chloroacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate(10.0 g, 27.48 mmol) in acetonitrile (200 mL) and stirred at 60° C. for16 h. The reaction mixture was concentrated to ⅕ volume, diluted withethyl acetate, and washed with water and brine prior to being dried(Na₂SO₄). Concentration gave J.31 (S)-tert-butyl2-(6-(2-azidoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate6.8 g (48%) as a golden orange foam. ¹H NMR (500 MHz, DMSO-d₆) δ:8.22/8.03 (s, 1H), 7.80-7.75 (m, 1H), 7.65/7.56 (d, J=8.5 Hz, 1H),4.99-4.93 (m, 3H), 3.60 (br. s, 1H), 3.46-3.41 (m, 1H), 2.38-2.27 (m,1H), 2.01-1.89 (m, 3H), 1.40/1.06 (s, 9H). LC (Cond.-D2): 1.97 min;LC/MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₃N₆O₃: 371.19. found: 371.32. HRMS:Anal. Calcd. for [M+H]⁺ C₁₈H₂₃N₆O₃: 371.1832. found: 371.1825.

To a solution of J.31 (1.8 g, 4.86 mmol) in ethyl acetate (5 mL) wasadded HCl/dioxane (10 mL of 4N), and the reaction was stirred 4 hr. Thesolvents were removed in vacuo, and the HCl salt was exposed to highvacuum for 18 h to give(S)-2-azido-1-(2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone.2HCla yellow solid. HATU (1.94 g, 5.10 mmol) was added to the HCl salt of(S)-2-azido-1-(2-(pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethanone(1.8 g, 4.86 mmol), (R)-2-(dimethylamino)-2-phenylacetic acid HCl salt(1.05 g, 4.86 mmol), and Hunig's base (3.4 mL, 19.4 mmol) indimethylformamide (50 mL) while being rapidly stirred 6 h. The solventwas removed in vacuo and the reside was partitioned into two lots andseparately pre-absorbed onto SiO₂ (dichloromethane), and subjected toflash chromatography on a 40 M Biotage silica gel columnpre-equilibrated 2% B, and eluted with 2% B (150 mL); Segment 2: 2-40% B(1200 mL); Segment 3: 40-80% (600 mL). A=dichloromethane; B=25%methanol/dichloromethane to give J.31a(R)-1-((S)-2-(6-(2-azidoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-(dimethylamino)-2-phenylethanone(combined lots: 1.05 g (50%)) as a yellow foam. ¹H NMR (500 MHz,DMSO-d₆) δ: 8.16 (s, 1H), 7.82 (dd, J=8.8, 1.5 Hz, 1H), 7.65 (d, J=8.5Hz, 1H), 7.60-7.56 (m, 5H), 5.51 (s, 1H), 5.22 (dd, J=8.2, 2.8, 1H),4.95 (m, 2H), 4.09-4.05 (m, 1H), 3.17-3.12 (m, 1H), 2.90/2.84 (br. s,6H), 2.23-2.19 (m, 1H), 2.21-1.89 (m, 3H). LC (D-Cond. 1): RT=1.5 min;LC/MS: Anal. Calcd. for [M+H]⁺ C₂₃H₂₆N₇O₂: 432.22. found: 431.93. HRMS:Anal. Calcd. for [M+H]⁺ C₂₃H₂₆N₇O₂: 432.2148. found: 432.2127.

Tin(II)dichloride dehydrate (12.24 g, 54.26 mmol) was added to J.31 (6.8g, 18.08 mmol) dissolved in methanol (200 mL). The reaction mixture washeated at 60° C. for 6 h and concentrated and dried under high vacuum togive the HCL salt of J.32 (S)-tert-butyl2-(6-(2-aminoacetyl)-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate,16.6 g which contained tin salts. LC (Cond.-D2): 1.21 min; LC/MS: Anal.Calcd. for [M+H]⁺ C₁₈H₂₅N₄O₃: 345.18. found: 345. The material was usedwithout purification.

J.32a

Examples J.33-J.34a

Tin(II)chloride dihydrate (17.25 g, 76.5 mmol) was added in one portionto methyl 2-amino-3-nitrobenzoate (5.0 g, 25.5 mmol) in methanol (100mL) under nitrogen. The yellow mixture was vigorously stirred at 65° C.for 16 h, and the solvent was removed by rotory evaporation to neardryness. The residue was taken up in ethyl acetate and the solution waspoured into a large beaker containing 1:1 ethyl acetate/NaHCO₃ soln.(300 mL) and stirred 15 min. The precipitates were removed by filtrationand the organic layer was separated. The aqueous layer was extractedtwice with ethyl acetate, and the combined organic layers were washedwith saturated NaHCO₃ solution, brine, and dried (Na₂SO₄). Concentrationgave methyl 2,3-diaminobenzoate as a deep red viscous oil 4.1 g (97%).

HATU (10.66 g, 28.0 mmol) was added in one portion to a stirred solutionof methyl 2,3-diaminobenzoate (4.1 g, 24.7 mmol), N-Boc-L-proline (5.49g, 25.5 mmol), and Hunig's base (4.9 mL, 28.0 mmol) in dimethylformamide(50 mL). The reaction mixture was stirred 3 h and solvent removed invacuo, and the residue was diluted with ethyl acetate, washed with 0.1NHCl, sat'd NaHCO₃, brine, and dried (Na₂SO₄). Concentration gave areddish brown viscous oil which was taken up in glacial acetic acid (60mL) and heated at 60° C. for 16 h. The solvent was removed in vacuo, andthe residue was diluted with ethyl acetate, washed with sat'd NaHCO₃soln., brine, and dried (Na₂SO₄). Concentration gave a residue that wasdivided into two lots, and each lot pre-adsorbed onto SiO₂(dichloromethane), applied to a 40 M Biotage SiO₂ column, and eluted bygradient 10%-100% B (1440 mL); A=hexanes; B=ethyl acetate to give J.33(S)-methyl2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazole-7-carboxylate7.05 g (83%) as a reddish oil. ¹H NMR (500 MHz, DMSO-d₆) δ: 7.86 (d,J=7.9 Hz, 1H), 7.78 (t, J=5 Hz, 1H), 7.28-7.24 (m, 1H), 5.20-5.11 (m,1H), 3.95 (s, 3H), 3.60-3.52 (m, 1H), 3.43-3.38 (m, 1H), 2.33-2.22 (m,1H), 2.15-2.0 (m, 2H), 1.91-1.86 (m, 1H), 1.40/1.05 (s, 9H). LC(Cond.-D2): RT=1.86 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₄N₃O₄:346.18. found 346.26; HRMS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₄N₃O₄:346.1767. found: 346.1776.

J.33a

RT = 0.72 min (Cond.-J3); LC/MS: Anal. Calcd. for [M + H]⁺ C₁₈H₂₄N₃O₄:346.18; found: 346.

Example J.34

A solution of 5N sodium hydroxide (8 mL) was added to methyl ester J.33(7.0 g, 20.3 mmol) in methanol (80 mL) and stirred 8 h. An additional 4mL was added and stirring continued stirring for 18 h, at which time thereaction temperature was raised to 45° C. for a final 8 h to completethe hydrolysis. Most of the methanol was removed by rotory evaporation,and the basic aqueous solution was diluted with ethyl acetate. Aprecipitate formed and was isolated by filtration. The organic layer wasseparated and washed with brine. Additional lots of precipitate formedduring partial concentration to ¼ vol, and the combined lots of J.34(S)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazole-7-carboxylicacid totaled 5.49 g (82%). ¹H NMR (500 MHz, DMSO-d₆) δ: 8.04-8.0 (m,2H), 7.58 (br. s, 1H), 5.32 (s, 1H), 3.67-3.63 (m, 1H), 3.47-3.43 (m,1H), 2.44-2.36 (m, 1H), 2.17-2.11 (m, 1H), 2.05-1.93 (m, 2H), 1.40/1.06(s, 9H). LC (Cond.-D2): 1.68 min; LC/MS: Anal. Calcd. for [M+H]⁺C₁₇H₂₂N₃O₄: 332.16. found: 332.25. HRMS: Anal. Calcd. for [M+H]⁺C₁₇H₂₂N₃O₄: 322.1610. found: 322.1625.

J.34a

RT = 1.64 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₁₇H₂₂N₃O₄:332.16; found: 332.14. HRMS: Anal. Calcd. for [M + H]⁺ C₁₇H₂₂N₃O₄:322.1605; found: 322.1603.

Examples J.35-J.35a

Iso-butyl chloroformate (0.45 mL, 3.4 mmol) was added dropwise to asolution of acid J.34 (1.0 g, 3.02 mmol) and N-methylmorpholine (1.2 mL,10 mmol) in tetrahydrofuran (50 mL) cooled at 0° C. under nitrogen, andthe ice bath was removed the reaction stirred 30 min. The solution wasrecooled and an additional 0.5 ml of base was added followed by of2-nitrophenacylamine.HCl (700 mg, 3.2 mmol). The reaction mixture wasstirred for 18 h at room temperature and diluted with ethyl acetate andsat'd NaHCO₃ soln. A precipitate was removed by filtration and theorganic phase was concentrated. The residue was taken up in methanol andfiltered to provide a second lot of precipitate. The combine lots ofJ.35, 796 mg (65%) were carried forward without further purification. ¹HNMR (300 MHz, DMSO-d₆) δ: 10.5 (br. s, 1H), 8.73 (s, 1H), 8.52-8.49 (m,1H), 7.88 (t, J=8.0 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.65 (d, J=7.7 Hz,1H), 7.25 (t, J=7.7 Hz, 1H), 5.11-5.05 (m, 3H), 3.70-3.33 (m, 2H),2.39-2.31 (m, 1H), 2.14-1.89 (m, 3H), 1.38/1.07 (s, 9H). LC (Cond.-J1):1.64 min; LRMS: Anal. Calcd. for [M+H]⁺ C₂₅H₂₈N₅O₆: 494.21. found:494.17.

J.35a

RT = 1.5 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₈N₅O₆:494.20; found 494.

Examples J.36-J.37e

N-(3-Dimethylaminopropyl)-N-ethylcarbodimide.HCl salt (3.1 g, 16.6 mmol)was added to a suspension of 3-amino-2-methylbenzoic acid (2.5 g, 16.6mmol) and N-Boc-L-proline (3.5 g, 16.6 mmol) in dichloromethane (40 mL).The reaction mixture was stirred under nitrogen for 18 h, diluted withsolvent (1 vol) and washed with 1N HCl, brine, and dried (MgSO₄).Concentration gave a foam with was applied to a 40 M Biotage SiO₂column, and eluted by gradient 20%-60% B (1000 mL); A=1% aceticacid/hexanes; B=1% acetic acid/ethyl acetate to give J.36(S)-3-(1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-2-methylbenzoicacid 2.6 g (45%). ¹H NMR (300 MHz, DMSO-d₆) δ: 12.5 (br. s, 1H),9.52/9.46 (s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.44-7.40 (m, 1H), 7.29-7.24(m, 1H), 4.32-4.28 (m, 1H), 3.47-3.48 (m, 1H), 3.34-3.29 (m, 1H), 2.33(s, 3H), 1.93-1.80 (m, 4H), 1.41/1.36 (s, 9H). LC (Cond.-J1): 1.55 min;LCMS: Anal. Calcd. for [M+H]⁺ C₁₈H₂₅N₂O₅: 349.18. found 349.33.

J.36a

RT = 2.12 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₁₇H₂₃N₂O₅:335.16; found 335.26. HRMS: Anal. Calcd. for [M − H]⁻ C₁₇H₂₁N₂O₅:333.1450; found: 333.1440. J.36b

RT = 2.14 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₁₈H₂₅N₂O₅:349.18; found 349.25. HRMS: Anal. Calcd. for [M + H]⁺ C₁₈H₂₅N₂O₅:349.1763; found: 349.1748. J.36c

RT = 2.09 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₁₇H₂₃N₂O₅:335.16; found 335.25. HRMS: Anal. Calcd. for [M − H]⁻ C₁₇H₂₃N₂O₅:333.1450; found: 333.1467. J.36d

RT = 2.24 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₁₇H₂₂FN₂O₅:353.15; found 353.22. HRMS: Anal. Calcd. for [M − H]⁻ C₁₇H₂₀FN₂O₅:351.1356; found: 351.1369.

HATU (462 mg, 1.22 mmol) was added in one portion to a stirred solutionof J.32 (450 mg, 1.22 mmol), J.36 (423 mg, 1.22 mmol), and Hunig's base(1.0 mL) in dimethylformamide (10 mL) and the reaction mixture wasstirred 18 h. The solvent was removed in vacuo and the residue wasapplied to a 25 M Biotage SiO₂ column, and eluted by gradient 5%-60% B(500 mL); A=ethyl acetate; B=10% methanol/ethyl acetate to give J.37,439.6 mg (50%). ¹H NMR (300 MHz, DMSO-d₆) δ: 12.73-12.58 (m, 1H),9.45/9.35 (s, 1H), 8.59 (br s, 1H), 8.33/8.12 (s, 1H) 7.86 (d, J=8.4 Hz,1H), 7.66/7.56 (d, J=8.4 Hz, 1H), 7.40-7.36 (m, 1H), 7.25 (app br. s,2H), 5.0-4.92 (m, 1H), 4.79 (d, J=4.8 H, 2H), 4.33-4.30 (m, 1H), 3.60(br. s, 1H), 3.47-3.41 (m, 2H), 3.35-3.29 (m, 1H), 2.24 (s, 3H),2.02-1.87 (m, 8H), 1.42-1.37/1.05 (m, 18H). LC (Cond.-J1): 1.65 min;LRMS: Anal. Calcd. for [M+H]⁺ C₃₆H₄₇N₆O₇: 675.35. found 675.30.

J.37a

RT = 2.29 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₅N₆O₇:661.34; found 661.42. J.37b

RT = 1.73 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₇N₆O₇:675.37; found 675.31. J.37c

RT = 2.24 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₅N₆O₇:661.34; found 661.42. J.37d

RT = 2.33 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₄FN₆O₇:679.33; found 679.42. J.37e

RT = 2.08 min (Cond.-D2); LCMS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₃N₆O₅:639.33; found 639.67.

Examples J.38-J.40

Tin(II)dichloride dihydrate (37 g, 168 mmol) was added to4-methyl-3-nitroacetophenone (10 g, 56 mmol) dissolved in methanol (350mL). The reaction mixture was heated at 60° C. for 18 h, concentrated,and dried under high vacuum to give to1-(3-amino-4-methylphenyl)ethanone which contained tin salts. LC(Cond.-J1): 0.73 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₉H₁₁NO: 150.08.found: 150. The material was used without purification. HATU (10.6 g, 28mmol) was added in one portion to a stirred solution of1-(3-amino-4-methylphenyl)ethanone (4.1 g, 28 mmol), N-Boc-L-proline (6g, 28 mmol), and Hunig's base (25 mL) in DMF (225 mL) and the reactionmixture was stirred 18 h. The solvent was removed in vacuo and theresidue was taken up in ethyl acetate/methanol (1:1) and applied to aflash SiO₂ column. A step elution by gradient 20%; 50%; 75%; 100% B(total elution vol 1500 mL); A=hexanes; B=ethyl acetate; and a finalelution with; 10% methanol/ethyl acetate was conducted to give J.38, 4.4g (46%). ¹H NMR (300 MHz, DMSO-d₆) δ: 9.51/9.45 (s, 1H), 7.95-7.92 (m,1H), 7.70 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.7 Hz, 1H), 4.33-4.29 (m, 1H),3.48-3.29 (m, 2H), 2.50 (s, 3H), 2.26 (s, 3H), 1.98-1.80 (m, 4H),1.41/1.36 (m, 9H). LC (Cond.-J1): 1.70 min; LRMS: Anal. Calcd. for[M+H]⁺ C₁₉H₂₇N₂O₄: 347.20. found 347.41.

Example J.38 (3 g, 83 mmol) was dissolved in methanol (30 mL) and 4NHCl/dioxane (50 mL) was added and the reaction was stirred 18 hr. Thesolvents were removed in vacuo, and(S)—N-(5-acetyl-2-methylphenyl)pyrrolidine-2-carboxamide HCl salt wasexposed to vacuum. LC (Cond-J1): 0.9 min. HATU (1.4 g, 3.5 mmol) wasadded in one portion to a stirred solution of(S)—N-(5-acetyl-2-methylphenyl)pyrrolidine-2-carboxamide.HCl (1.0 g, 3.5mmol), (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (740 mg, 3.5mmol), and Hunig's base (2.9 mL) in dimethylformamide (25 mL) and thereaction mixture was stirred 18 h. The solvent was removed in vacuo andthe residue was applied to a 40 M Biotage SiO₂ column, and eluted bygradient 50%-100% B (500 mL); A=hexanes; B=ethyl acetate to give J.39,methyl(R)-2-((S)-2-(5-acetyl-2-methylphenylcarbamoyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate1.25 g (87%). ¹H NMR (300 MHz, DMSO-d₆) δ: 9.42 (s, 1H), 7.95 (s, 1H),7.75-7.69 (m, 2H), 7.43-7.19 (m, 6H), 5.50/5.40 (d, J=7.7 Hz, 1H),4.49-4.47 (m, 1H), 3.87-3.81 (m, 1H), 3.58-3.54 (m, 1H), 3.50 (s, 3H),2.54 (s, 3H), 2.27 (s, 3H), 1.99-1.83 (m, 4H). LC (Cond.-J1): 1.65 min;LRMS: Anal. Calcd. for [M+H]⁺ C₂₄H₂₈N₃O₅: 438.20. found 438.20.

Reference: Synthesis (1988) p 545. (Chlorination).

Benzyltrimethyldichloroiodate (2.0 g, 5.72 mmol) was added to a solutionof J.39 (1.25 g, 2.86 mmol) in dichloromethane (65 mL) and methanol (20mL). The reaction was heated for 3 h at 75° C. before being concentratedby rotory evaporation. The residue was taken up in ethyl acetate andwashed with sodium thiosulfate soln, brine, and dried (MgSO₄) to affordan α-chloroketone. LC (Cond.-J1): 1.70 min; LC/MS: Anal. Calcd. for[M+H]⁺ C₂₄H₂₇ClN₃O₅: 471.16. found: 471.

The α-chloroketone was converted to the α-aminoketone J.40 as describedin example J.31. [α-azidoketone: LC (Cond.-J1): 1.70 min; LRMS: Anal.Calcd. for [M+H]⁺ C₂₄H₂₇N₆O₅: 479.20. found: 479.20.] J.26 LC(Cond.-J1): 1.70 min; LRMS: Anal. Calcd. for [M+H]⁺ C₂₄H₂₉N₄O₅: 453.21.found: 453.

Example J.41-J.42h

The α-aminoketone J.40 was coupled with J.34a as described in exampleJ.37 to give J.41: LC (Cond.-J1): 1.90 min; LRMS: Anal. Calcd. for[M+H]⁺ C₄₁H₄₈N₇O₈: 766.36. found: 766.37.

J.41a

RT = 1.64 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₅N₆O₇:661.34; found 661.30. J.41b

RT = 1.82 min (Cond.-J1); LCMS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₅N₆O₇:661.34; found 661.32.

A solution of J.41 (237 mg, 0.31 mmol), triphenylphosphine (162 mg, 0.62mmol), and triethylamine (0.2 mL, 1.74 mmol) in dichloromethane (3 mL)was stirred about 5 min under nitrogen atmosphere before addition ofhexachloroethane (146 mg, 0.62 mmol) in one portion. The reactionmixture was stirred 18 h, partially concentrated, and applied to a 12 MBiotage silica gel column and eluted by gradient 40%-100% B. A=hexanes;B=ethyl acetate to give J.42, 95 mg (41%). LC (Cond.-J1): 1.95 min;LRMS: Anal. Calcd. for [M+H]⁺ C₄₁H₄₆N₇O₇: 748.36. found: 748.29.

J.42a

RT = 2.64 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₃N₆O₆:643.32; found: 643.35. HRMS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₃N₆O₆:643.3244; found 643.3242. J.42b

RT = 2.97 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₃N₆O₆:643.32; found: 643.37. HRMS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₃N₆O₆:643.3244; found 643.3265. J.42c

RT = 2.51 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₅N₆O₆:657.34; found: 657.36. HRMS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₅N₆O₆:657.3401; found 657.3407. J.42d

RT = 2.61 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₃N₆O₆:643.32; found: 643.41. J.42e

RT = 2.63 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₅N₆O₆:657.34; found: 657.73. HRMS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₅N₆O₆:657.3401; found 657.3397. J.42f

RT = 1.59 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₃N₆O₆:643.32; found: 643.41. J.42g

RT = 2.64 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₅H₄₂FN₆O₆:661.32; found: 661.40. J.42h

RT = 2.41 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₁N₆O₄:621.32; found: 621.21.

Examples J.43-J.43j

The pyrrolidines examples J.42-J.42h were treated with HCl as describedin example J.39 to give examples J.43-J.43j as HCl salts.

J.43

RT = 1.80 min (Cond.-J1) LCMS: Anal. Calcd. for [M + H]⁺ C₃₆H₃₈N₇O₅:648.29; found 648. J.43a

RT = 1.69 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₇N₆O₂:443.22; found: 443.23. J.43b

RT = 1.86 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₇N₆O₂:443.22; found: 443.07. HRMS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₇N₆O₂:443.2195; found 443.2213. J.43c

RT = 1.51 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₆H₂₉N₆O₂:457.24; found: 457.19. J.43d

RT = 1.64 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₇N₆O₂:443.22; found: 443.31. HRMS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₇N₆O₂:443.2195; found 443.2205. J.43e

RT = 1.70 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₆H₂₉N₆O₂:457.24; found: 457.29. HRMS: Anal. Calcd. for [M + H]⁺ C₂₆H₂₉N₆O₂:457.2352; found 457.2332. J.43f

RT = 1.59 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₇N₆O₂:443.22; found: 443.31. HRMS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₇N₆O₂:443.2195; found 443.2206. J.43g

RT = 1.61 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₆FN₆O₂:461.21; found: 461.31. HRMS: Anal. Calcd. for [M + H]⁺ C₂₅H₂₆FN₆O₂:461.2101; found 461.2101. J.43h

RT = 1.70 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₁H₃₃N₆O₂:521.27; found: 521.48. HRMS: Anal. Calcd. for [M + H]⁺ C₃₁H₃₃N₆O₂:521.2665; found 521.2673. J.43i

RT = 2.33 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₈N₇O₅:718.37; found: 718.19. HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₄₈N₇O₅:718.3717; found 718.3692. J.43j

RT = 1.69 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₆H₄₀N₇O₃:618.32; found: 618.38.

Examples J.44-J.53a

Examples J.44-J.53a were prepared as described in example J.21.

J.44

RT = 1.91 min (Cond.-J1) LRMS: Anal. Calcd. for [M + H]⁺ C₄₆H₄₇N₈O₈:839.35; found 839.29. HRMS: Anal. Calcd. for [M + H]⁺ C₄₆H₄₇N₈O₈:839.3517; found 839.3492. J.44a

RT = 1.80 min (Cond.-J1) LRMS: Anal. Calcd. for [M + H]⁺ C₄₆H₄₉N₈O₆:809.38; found 809.29. HRMS: Anal. Calcd. for [M + H]⁺ C₄₆H₄₉N₈O₆:809.3775; found 809.3768. J.45

RT = 2.42 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₅N₈O₈:825.34; found: 825.40. HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₅N₈O₈:825.3360; found 825.3366. J.45a

RT = 2.27 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₉N₉O₄:765.39; found: 765.36. HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₉N₈O₄:765.3877; found 765.3879. J.45b

RT = 2.48 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₃₉N₆O₄:679.30; found: 679.37. HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₃₉N₆O₄:679.3033; found 679.3037. J.46

RT = 2.10 min (D-Cond. 2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₉N₈O₄:765.39; found: 765.72. HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₉N₈O₄:765.3877; found 765.3899. J.47

RT = 1.77 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₆H₅₁N₈O₄:779.40; found: 779.49. HRMS: Anal. Calcd. for [M + H]⁺ C₄₆H₅₁N₈O₄:779.4033; found: 779.4042. J.47a

RT = 2.28 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₆H₄₇N₈O₈:839.35; found: 839.43. HRMS: Anal. Calcd. For [M + H]⁺ C₄₆H₄₇N₈O₈:839.3517; found: 839.3519. J.48

RT = 2.21 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₁H₃₉N₆O₆:711.29; found: 711.46. HRMS: Anal. Calcd. for [M + H]⁺ C₄₁H₃₉N₆O₆:711.2931; found: 711.2942. J.48a

RT = 2.37 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₉N₈O₈:757.37; found: 757.37. HRMS: Anal. Calcd. for [M + H]⁺ C₃₉H₄₉N₈O₈:757.3673; found: 757.3705. J.48b

RT = 1.92 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₉N₈O₄:765.39; found: 765.59. HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₉N₈O₄:765.3877; found: 765.3841. J.48c

RT = 2.26 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₅N₈O₆:793.35; found: 793.52. HRMS: Anal. Calcd. for [M + H]⁺ C₄₅H₄₅N₈O₆:793.3462; found: 793.3452. J.48d

RT = 2.88 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺C₄₇H₃₉Cl₂N₈O₆: 881.24; found: 881.50. HRMS: Anal. Calcd. for [M + H]⁺C₄₇H₃₉Cl₂N₈O₆: 881.2370; found: 881.2347. J.49

RT = 2.41 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₄₆H₄₇N₈O₈:839.35; found: 839.27. HRMS: Anal. Calcd. for [M + H]⁺ C₄₆H₄₇N₈O₈:839.3517; found: 839.3535. J.49a

RT = 2.07 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C46H51N8O4:779.40; found: not apparent. HRMS: Anal. Calcd. for [M + H]⁺ C46H51N8O4:779.4033; found: 779.4014. J.50

RT = 2.26 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C41H39N6O6:711.29; found: 711.39. HRMS: Anal. Calcd. for [M + H]⁺ C41H39N6O6:711.2931; found: 711.2958. J.50a

RT = 1.92 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C45H49N8O4:765.39; found: 765.53. HRMS: Anal. Calcd. for [M + H]⁺ C45H49N8O4:765.3877; found: 765.3843. J.50b

RT = 2.29 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C45H45N8O6:793.35; found: 793.49. HRMS: Anal. Calcd. for [M + H]⁺ C45H45N8O6:793.3462; found: 793.3442. J.50c

RT = 2.99 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺C47H39Cl2N8O6: 881.42; found: 883.41. HRMS: Anal. Calcd. for [M + H]⁺C47H39Cl2N8O6: 881.2370; found: 881.2349. J.51

RT = 2.29 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C41H38FN6O6:729.28; found: 729.36. HRMS: Anal. Calcd. for [M + H]⁺ C41H38FN6O6:729.2837; found: 729.2847. J.51a

RT = 1.93 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C45H48FN8O4:783.38; found: 783.52. HRMS: Anal. Calcd. for [M + H]⁺ C45H48FN8O4:783.3783; found: 783.3764. J.51b

RT = 2.89 min (Cond.-D2); LRMS: Anal. Calcd. for [M + H]⁺ C47H38ClFN8O6:899.23; found: 897.19. HRMS: Anal. Calcd. for [M + H]⁺ C47H38ClFN8O6:899.2275; found: 899.2287. J.52

RT = 2.23 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C44H46N7O4:736.36; found: 737.00. HRMS: Anal. Calcd. for [M + H]⁺ C44H46N7O4:736.3611; found: 736.3622. J.52a

RT = 1.75 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C40H47N8O4:703.37; found: 703.81. HRMS: Anal. Calcd. for [M + H]⁺ C40H47N8O4:703.3720; found: 703.3748. J.52b

RT = 2.22 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C46H49N8O6:809.38; found: 809.57. HRMS: Anal. Calcd. for [M + H]⁺ C46H49N8O6:809.3775; found: 809.3803. J.52c

RT = 2.27 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C43H51N8O6:775.39; found: 775.39. HRMS: Anal. Calcd. for [M + H]⁺ C43H51N8O6:775.3932; found: 775.3921. J.52d

RT = 2.09 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C41H47N8O6:747.36; found: 747.34. HRMS: Anal. Calcd. for [M + H]⁺ C41H47N8O6:747.3619; found: 747.3610. J.53

RT = 2.22 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₅H₃₉N₆O₄:607.30; found: 607.71. HRMS: Anal. Calcd. for [M + H]⁺ C₃₅H₃₉N₆O₄:607.3033; found: 607.3015. J.53a

RT = 2.28 min (Cond.-D2); LC/MS: Anal. Calcd. for [M + H]⁺ C₃₅H₃₉N₆O₄:607.30; found: 607.34.

BIOLOGICAL ACTIVITY

An HCV Replicon assay was utilized in the present disclosure, and wasprepared, conducted and validated as described in commonly ownedPCT/US2006/022197 and in O'Boyle et. al. Antimicrob Agents Chemother.2005 April; 49(4):1346-53. Assay methods incorporating luciferasereporters have also been used as described (Apath.com).

HCV-neo replicon cells and replicon cells containing mutations in theNS5A region were used to test the currently described family ofcompounds. The compounds were determined to have more than 10-fold lessinhibitory activity on cells containing mutations than wild-type cells.Thus, the compounds of the present disclosure can be effective ininhibiting the function of the HCV NS5A protein and are understood to beas effective in combinations as previously described in applicationPCT/US2006/022197 and commonly owned WO/04014852. Further, the compoundsof the present disclosure can be effective against the HCV 1b genotype.It should also be understood that the compounds of the presentdisclosure can inhibit multiple genotypes of HCV. Table 2 shows the EC₅₀(Effective 50% inhibitory concentration) values of representativecompounds of the present disclosure against the HCV 1b genotype. In oneembodiment, compounds of the present disclosure are inhibitory versus1a, 1b, 2a, 2b, 3a, 4a, and 5a genotypes. EC₅₀ values against HCV 1b areas follows A (1-10 μM); B (100-999 nM); C (4.57-99 nM); D (2 pM-4.57nM).

The compounds of the present disclosure may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present disclosure inhibit HCV replicon and in anotherembodiment the compounds of the present disclosure inhibit NS5A.

TABLE 2 Example EC50 Range Name J.21 D methyl((1S)-1-(((2S)-2-(8-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-1,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.21a D(1R)-2-((2S)-2-(8-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine J.22 D methyl((1S)-1-(((2S)-2-(5-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.22a D(1R)-2-((2S)-2-(4-(4-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1- phenylethanamineJ.22b D methyl ((1R)-2-((2S)-2-(4-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate J.23 D methyl((1S)-1-(((2S)-2-(5-(3-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.23a D(1R)-2-((2S)-2-(4-(3-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1- phenylethanamineJ.23b D methyl ((1R)-2-((2S)-2-(4-(3-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate J.24 10 pM D methyl((1S)-1-(((1R,3S,5R)-3-(8-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-1,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate J.25 Dmethyl ((1S)-1-(((2S)-2-(5-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-4,5-dihydro-3H-naphtho[1,2-d]imidazol-7-yl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.26 5 pM Dmethyl ((1S)-1-(((2S)-2-(5-(4′-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)-4-biphenylyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.27 D methyl((1S)-1-(((2S)-2-(5-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-3H-naphtho[1,2-d]imidazol-7-yl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.27a D(1R)-2-((2R)-2-(7-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine J.27b D methyl((1S)-1-(((2S)-2-(5-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.27c 3.0 pM Dmethyl ((1R)-2-((2S)-2-(7-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate J.28 D methyl((1S)-1-(((2S)-2-(5-((4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)ethynyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.28a D(1R)-2-((2S)-2-(4-(4-((2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine J.28a.1 D methyl((1S)-1-(((2S)-2-(5-((4-(4-ethyl-2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)ethynyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.28a.2 D methyl((1S)-1-(((2S)-2-(4-(cyanomethyl)-5-(4-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamate J.28bD methyl ((1S)-1-(((1R,3S,5R)-3-(5-((4-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)phenyl)ethynyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate J.28c D methyl((1S)-1-(((1R,3S,5R)-3-(4-(4-((4-fluoro-2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-6-yl)ethynyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate J.28d D methyl((1S)-1-(((1R,3S,5R)-3-(4-(2-fluoro-4-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)phenyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate J.28e D methyl((1S)-1-(((2S)-2-(5-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-4,5-dihydro-3H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamateJ.28e.1 D methyl ((1R)-2-((2S)-2-(7-((2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate J.28f Dmethyl ((1S)-1-(((2S)-2-(5-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-3H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.28f.1 D methyl((1R)-2-((2S)-2-(7-((2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate J.28g D methyl((1S)-1-(((2S)-2-(4-fluoro-6-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamateJ.28h 120 pM D methyl ((1S)-1-(((2S)-2-(4-fluoro-6-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.28h.1 D methyl((1S)-1-(((1R,3S,5R)-3-(5-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate J.28h.2 Dmethyl ((1R)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamate J.28i D methyl((1S)-1-(((1R,3S,5R)-3-(5-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate J.28i.1 D methyl((1R)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamate J.28i.2 0.51 pM D methyl((1S)-1-(4,4-difluorocyclohexyl)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2S)-2-(4,4-difluorocyclohexyl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)carbamate J.28i.3 D methyl((1S)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate J.28i.4 D methyl((1S)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate J.28j D methyl((1S)-1-(((1R,3S,5R)-3-(4-fluoro-6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate J.28k Dmethyl ((1S)-1-(((1R,3S,5R)-3-(4-fluoro-6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate J.28k.1 D benzyl(1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-(N-(methoxycarbonyl)-L-valyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate J.28l 7 nM C methyl((1S)-1-(((2S)-2-(5-(3-((2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)phenyl)-1H-imidazol-4-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.28m 55.7 nM C(1R)-2-((2S)-2-(5-(3-((2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)phenyl)-1H-imidazol-4-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine J.28n D methyl((1S)-1-(((2S)-2-(5-((4-(4-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)ethynyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.28o D methyl((1S)-1-(((2S,5S)-2-(5-((2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate J.28p D methyl((1S)-2-((2S,5S)-2-(7-((2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-5-methyl-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate JB.8 D methyl((1S)-1-(((2S)-2-(4-((4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate JB.8.1 B methyl((1R)-1-(((2S)-2-(4-((4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate JB.9 D methyl((1S)-2-((2S)-2-(5-(4-((2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2- oxoethyl)carbamate JB.10D methyl ((1S,2R)-2-methoxy-1-(((2S)-2-(5-(4-((2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate JB.11 D methyl((1R)-2-((2S)-2-(4-((4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate JB.12 65.2 pM D2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-5-(4-((2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)phenyl)-1H-benzimidazole J.28r 15.5 pM D methyl((1S)-1-(((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate J.28s D methyl((1S)-2-((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate JB.15 D methyl((1S)-1-(((2S)-2-(4-(2-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate M.8 46.4 nM C(S)-1-acetyl-N-(4-((2-((S)-1-(2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethynyl)phenyl)pyrrolidine-2- carboxamide M.9 C(S)-1-(2-phenylacetyl)-N-(4-((2-((S)-1-(2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethynyl)phenyl)pyrrolidine-2-carboxamide M.10 202 nM B(S)-1-acetyl-N-(4-(2-(2-((S)-1-(2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethyl)phenyl)pyrrolidine-2- carboxamide M.11 C(S)-1-(2-phenylacetyl)-N-(4-(2-(2-((S)-1-(2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)ethyl)phenyl)pyrrolidine-2-carboxamide J.44 D methyl((1R)-2-((2S)-2-((5-(2-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-5-yl)-2-methylphenyl)carbamoyl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamateJ.44a D methyl (R)-2-((S)-2-(5-(2-(2-((S)-1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)oxazol-5-yl)-2-methylphenylcarbamoyl)pyrrolidin-1-yl)-2-oxo-1-phenylethylcarbamate J.45 D methyl((1R)-2-((2S)-2-((3-(2-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-5-yl)phenyl)carbamoyl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate J.45a D1-((2R)-2-(dimethylamino)-2-phenylacetyl)-N-(3-(2-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-5-yl)phenyl)-L-prolinamide J.45b D(S)-1-(2-phenylacetyl)-N-(3-(2-(2-((S)-1-(2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-5-yl)oxazol-5-yl)phenyl)pyrrolidine-2-carboxamide J.46 D(S)-1-((R)-2-(dimethylamino)-2-phenylacetyl)-N-(3-(2-(2-((S)-1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-4-yl)oxazol-5-yl)phenyl)pyrrolidine-2- carboxamide J.47D 1-((2R)-2-(dimethylamino)-2-phenylacetyl)-N-(3-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-methylphenyl)-L- prolinamide J.47aD methyl ((1R)-2-((2S)-2-((3-(5-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-methylphenyl)carbamoyl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamateJ.48 D 1-((2R)-2-hydroxy-2-phenylacetyl)-N-(3-(5-(2-((2S)-1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide J.48a D methyl((1S)-1-(((2S)-2-(5-(2-(3-((((2S)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-1-pyrrolidinyl)carbonyl)amino)phenyl)-1,3-oxazol-5-yl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2- methylpropyl)carbamateJ.48b C (2R)-2-(dimethylamino)-N-(3-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-2-phenylacetamide J.48c D1-((2R)-2-acetamido-2-phenylacetyl)-N-(3-(5-(2-((2S)-1-((2R)-2-acetamido-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide J.48d 147 nM B1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-N-(3-(5-(2-((2S)-1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide J.49 D methyl ((1R)-2-((2S)-2-((5-(5-(2-(1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-methylphenyl)carbamoyl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamateJ.49a D (S)-1-((R)-2-(dimethylamino)-2-phenylacetyl)-N-(5-(5-(2-((S)-1-((R)-2-(dimethylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)oxazol-2-yl)-2-methylphenyl)pyrrolidine-2-carboxamide J.50 C1-((2R)-2-hydroxy-2-phenylacetyl)-N-(4-(5-(2-((2S)-1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide J.50a D1-((2R)-2-(dimethylamino)-2-phenylacetyl)-N-(4-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide J.50b D1-((2R)-2-acetamido-2-phenylacetyl)-N-(4-(5-(2-((2S)-1-((2R)-2-acetamido-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide J.50c >10 μM A1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-N-(4-(5-(2-((2S)-1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide J.51 CN-(2-fluoro-4-(5-(2-((2S)-1-((2R)-2-hydroxy-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-1-((2R)-2-hydroxy-2-phenylacetyl)-L-prolinamide J.51a D1-((2R)-2-(dimethylamino)-2-phenylacetyl)-N-(4-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-fluorophenyl)-L- prolinamide J.51bB 1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-N-(4-(5-(2-((2S)-1-((3-chloro-5-methoxy-1-isoquinolinyl)carbonyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-fluorophenyl)-L-prolinamide J.52 DN-(5-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-methylphenyl)-1-(phenylacetyl)-L-prolinamide J.52a CN,N-dimethylglycyl-N-(5-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-methylphenyl)-L- prolinamide J.52bD methyl ((1R)-2-((2S)-2-((5-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-methylphenyl)carbamoyl)-1-pyrrolidinyl)-2-oxo-1- phenylethyl)carbamateJ.52c D N-(methoxycarbonyl)-L-valyl-N-(5-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-methylphenyl)-L- prolinamide J.52dD N-(methoxycarbonyl)-L-alanyl-N-(5-(5-(2-((2S)-1-((2R)-2-(dimethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)-2-methylphenyl)-L- prolinamide J.53B 1-(cyclopropylacetyl)-N-(3-(5-(2-((2S)-1-(cyclopropylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide J.53a A1-(cyclopropylacetyl)-N-(3-(2-(2-((2S)-1-(cyclopropylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-5-yl)phenyl)-L-prolinamide

It will be evident to one skilled in the art that the present disclosureis not limited to the foregoing illustrative examples, and that it canbe embodied in other specific forms without departing from the essentialattributes thereof. It is therefore desired that the examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing examples, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

The compounds of the present disclosure may inhibit HCV by mechanisms inaddition to or other than NS5A inhibition. In one embodiment thecompounds of the present disclosure inhibit HCV replicon and in anotherembodiment the compounds of the present disclosure inhibit NS5A.Compounds of the present disclosure may inhibit multiple genotypes ofHCV.

What is claimed is:
 1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein each m isindependently 0 or 1; each n is independently 0 or 1; L is a bond or isselected from

wherein each group is drawn with its left end attached to thebenzimidazole and its right end attached to R¹; R¹ is selected from

each R² is independently selected from alkyl and halo; each R³ isindependently selected from hydrogen and —C(O)R⁷; R⁴ is alkyl; R⁵ and R⁶are independently selected from hydrogen, alkyl, cyanoalkyl, and halo,or R⁵ and R⁶, together with the carbon atoms to which they are attached,form a six- or seven-membered ring optionally containing one heteroatomselected from nitrogen and oxygen and optionally containing anadditional double bond; and each R⁷ is independently selected fromalkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl, (cycloalkyl)alkyl,heterocyclyl, heterocyclylalkyl, (NR^(c)R^(d))alkenyl, and(NR^(c)R^(d))alkyl; provided that when L is other than

and R¹ is other than

then either at least one of R⁵ and R⁶ is alkyl or cyanoalkyl, or atleast one R⁷ is arylalkoxy or (cycloalkyl)alkyl.
 2. A compound of claim1, or a pharmaceutically acceptable salt thereof, wherein L is selectedfrom

and R¹ is


3. A compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein one of R⁵ and R⁶ is alkyl or cyanoalkyl.
 4. A compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R⁷ is selectedfrom arylalkoxy and (cycloalkyl)alkyl.
 5. A compound selected frommethyl((1S)-1-(((2S)-2-(8-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)-1,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;(1R)-2-((2R)-2-(7-(2-((2S)-1-((2R)-2-(diethylamino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-N,N-diethyl-2-oxo-1-phenylethanamine;methyl((1S)-1-(((2S)-2-(5-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-naphtho[1,2-d]imidazol-7-yl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;methyl((1R)-2-((2S)-2-(7-(4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;methyl((1S)-1-(((2S)-2-(5-((4-(4-ethyl-2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-imidazol-5-yl)phenyl)ethynyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;methyl((1S)-1-(((2S)-2-(4-(cyanomethyl)-5-(4-((2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;methyl((1R)-2-((2S)-2-(7-((2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;methyl((1R)-2-((2S)-2-(7-((2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;methyl((1S)-1-(((1R,3S,5R)-3-(5-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;methyl((1R)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamate;methyl((1R)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamate;methyl((1S)-1-(4,4-difluorocyclohexyl)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2S)-2-(4,4-difluorocyclohexyl)-2-((methoxycarbonyl)amino)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxoethyl)carbamate;methyl((1S)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;methyl((1S)-2-((1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;methyl((1S)-1-(((1R,3S,5R)-3-(4-fluoro-6-((2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate; benzyl(1R,3S,5R)-3-(7-((2-((1R,3S,5R)-2-(N-(methoxycarbonyl)-L-valyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo [3.1.0]hexane-2-carboxylate; methyl((1S)-1-(((2S,5S)-2-(5-((2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-5-methyl-2-pyrrolidinyl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-1H-benzimidazol-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;methyl((1S)-2-((2S,5S)-2-(7-((2-((2S,5S)-1-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-5-methyl-2-pyrrolidinyl)-1H-benzimidazol-5-yl)ethynyl)-1H-naphtho[1,2-d]imidazol-2-yl)-5-methyl-1-pyrrolidinyl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;methyl((1S)-1-((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate; methyl((1S)-2-((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;methyl((1S)-1-(((2S)-2-(4-((4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;methyl((1R)-1-(((2S)-2-(4-((4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;methyl((1S)-2-((2S)-2-(5-(4-((2-((2S)-1-(N-(methoxycarbonyl)-L-alanyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)-1-methyl-2-oxoethyl)carbamate;methyl((1S,2R)-2-methoxy-1-(((2S)-2-(5-(4-((2-((2S)-1-(N-(methoxycarbonyl)-O-methyl-L-threonyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)phenyl)-1H-benzimidazol-2-yl)-1-pyrrolidinyl)carbonyl)propyl)carbamate;methyl((1R)-2-((2S)-2-(4-((4-(2-((2S)-1-((2R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethynyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)carbamate;2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-5-(4-((2-((2S)-1-((2R)-2-phenyl-2-(1-piperidinyl)acetyl)-2-pyrrolidinyl)-1H-imidazol-4-yl)ethynyl)phenyl)-1H-benzimidazole;methyl((1S)-1-(((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate;methyl((1S)-2-((1R,3S,5R)-3-(7-(2-(2-((1R,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)ethyl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate;methyl((1S)-1-(((2S)-2-(4-(2-(4-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)phenyl)ethyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;1-(cyclopropylacetyl)-N-(3-(5-(2-((2S)-1-(cyclopropylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-2-yl)phenyl)-L-prolinamide;and1-(cyclopropylacetyl)-N-(3-(2-(2-((2S)-1-(cyclopropylacetyl)-2-pyrrolidinyl)-1H-benzimidazol-5-yl)-1,3-oxazol-5-yl)phenyl)-L-prolinamide;or a pharmaceutically acceptable salt thereof.
 6. A compositioncomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 7. The compositionof claim 6 further comprising one or two additional compounds havinganti-HCV activity.
 8. The composition of claim 7 wherein at least one ofthe additional compounds is an interferon or a ribavirin.
 9. Thecomposition of claim 8 wherein the interferon is selected frominterferon alpha 2B, pegylated interferon alpha, consensus interferon,interferon alpha 2A, and lymphoblastoid interferon tau.
 10. Thecomposition of claim 7 wherein at least one of the additional compoundsis selected from interleukin 2, interleukin 6, interleukin 12, acompound that enhances the development of a type 1 helper T cellresponse, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, aninosine 5′-monophospate dehydrogenase inhibitor, amantadine, andrimantadine.
 11. The composition of claim 7 wherein at least one of theadditional compounds is effective to inhibit the function of a targetselected from HCV metalloprotease, HCV serine protease, HCV polymerase,HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCVNS5A protein, and IMPDH for the treatment of an HCV infection.
 12. Amethod of treating an HCV infection in a patient, comprisingadministering to the patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof. 13.The method of claim 12 further comprising administering one or twoadditional compounds having anti-HCV activity prior to, after orsimultaneously with the compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 14. The method of claim 13 wherein at least oneof the additional compounds is an interferon or a ribavirin.
 15. Themethod of claim 14 wherein the interferon is selected from interferonalpha 2B, pegylated interferon alpha, consensus interferon, interferonalpha 2A, and lymphoblastoid interferon tau.
 16. The method of claim 13wherein at least one of the additional compounds is selected frominterleukin 2, interleukin 6, interleukin 12, a compound that enhancesthe development of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiqimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.
 17. The method ofclaim 13 wherein at least one of the additional compounds is effectiveto inhibit the function of a target selected from HCV metalloprotease,HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCVentry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for thetreatment of an HCV infection.